Methods for Making Controlled Delivery Devices Having Zero Order Kinetics

ABSTRACT

A method of making an injectable or implantable active agent delivery device capable of delivering a diagnostic, therapeutic, and/or prophylactic agent to a desired targeted site having orifice(s) on the surface is disclosed herein providing unidirectional release of the agent at a controlled desirable rate. The agent may include, but is not limited to, drugs, proteins, peptides, biomarkers, bioanalytes, and/or genetic material. The technology of the invention is based on parallel processing to fabricate micro-holes on tubes employing photo-lithography and reactive ion etching techniques and also incorporates a simple molding method to form the micro-holes on flexible polymer tubes, including bio-degradable tubes. The parallel processing method of the instant invention is fast, economical and well suited for mass production. The developed device, due to its composite structure, has the ability to combine several release mechanisms, leading to zero-order release kinetics for most of the time.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/612,578, filed Feb. 3, 2015, which is a continuation of U.S. patentapplication Ser. No. 13/383,820, filed Mar. 20, 2012, which is aNational Stage of International Application No. PCT/US2010/042030, filedJul. 14, 2010, and also is a continuation of U.S. patent applicationSer. No. 13/383,810, filed Feb. 13, 2012, which is a National Stage ofInternational Application No. PCT/US2010/042029, filed Jul. 14, 2010,both of which claim the benefit of U.S. Provisional Application Nos.61/225,309 and 61/225,352, both filed Jul. 14, 2009. The contents ofeach of the applications are incorporated by reference in theirentirety.

TECHNICAL FIELD OF THE INVENTION

This invention relates to methods for making a therapeutic agentdelivery device that is capable of delivering a diagnostic, therapeutic,and/or prophylactic agent. Optionally, the delivery device may monitorbodily fluid analytes by incorporation of microelectronics.Additionally, the release of the agent from the device is unidirectionaland at a controlled desirable rate. For example, the agent may include,but is not limited to, drugs, proteins, peptides, biomarkers,bioanalytes, and/or genetic material.

BACKGROUND ART

A number of implantable drug delivery devices have been suggested to becapable of delivering the drug to the body lumen. One universaladvantage to implanted drug delivery devices is related to the localadministration of a drug that inherently improves efficacy and decreasesside effects, when compared to other routes of administration such asoral, rectal, topical, or systemic.

Nonetheless, a problem with the known implantable drug delivery devicesis that the delivery rate cannot be controlled during all operationalphases of the devices (i.e., drug delivery rates may change therebyresulting in, for example, first order delivery kinetics or second orderdelivery kinetics). Such problems result in a drug delivery device thatadministers drugs in an unpredictable pattern, thereby resulting in poortherapeutic benefit.

For example, a popular drug delivery device is a drug eluting stent.Stents are mesh-like steel or plastic tubes that are used to open up aclogged atherosclerotic coronary artery or a blood vessel undergoingstenosis. A drug may be attached onto, or impregnated into, the stentthat is believed to prevent re-clogging or restenosis a blood vessel.However, the initial release of the drug may be very rapid releasing20-40% of the total drug in a single day. Such high concentrations ofthe drug have been reported to result in cytotoxicity at the targetedsite.

As a result of these problems, there is a need for a drug deliverydevice, which can be optimized to deliver any therapeutic, diagnostic,or prophylactic agent for any time period up to several yearsmaintaining a controlled and desired rate.

SUMMARY OF THE INVENTION

This invention relates to methods of making a therapeutic agent deliverydevice that is capable of delivering a diagnostic, therapeutic, and/orprophylactic agent to a desired targeted site. Optionally, the deliverydevice may monitor bodily fluid analytes. Additionally, the release ofthe agent from the device is unidirectional and at a controlled anddesirable rate. For example, the agent may include, but is not limitedto, drugs, proteins, peptides, biomarkers, bioanalytes, and/or geneticmaterial.

In one embodiment the present invention discloses a method for making adevice for delivery of one or more active agents with zero-orderkinetics comprising the steps of: providing a mold comprising a firstsurface and a second surface, wherein the first surface comprises one ormore trenches, cavities or depressions, wherein each of the one or moretrenches, cavities or depressions comprise one or more holes orperforations, placing a first substrate in the trenches, cavities ordepressions, wherein the substrate may optionally be held in place inthe trench by using an adhesive, and transferring a shape of the holesor the perforations in the one or more trenches, cavities or depressionsto the first substrate by one or more microfabrication techniques tomake the device for the delivery of the one or more active agents. Theshape of the one or more holes or perforations as described in theinstant invention is selected from the group consisting of a triangle, apolygon, an undecagon, a trapezium or trapezoid, a quadrilateral, anicosagon, a star polygon, an annulus, a circle, a crescent, an ellipse,an oval, an arbelos, a Reuleaux triangle, a semicircle, a sphere, anArchimedean spiral, an astroid, a deltoid, a super ellipse, and atomahawk. The one or more microfabrication techniques listed hereinaboveare selected from the group consisting of physical etching, chemicaletching, reactive ion etching, physical vapor deposition, chemical vapordeposition, liftoff, electroplating, electroless plating, ion milling,laser ablation, plasma torch cutting, lithography, and combinations andmodifications thereof.

The method of the present invention further comprises two optionalsteps: (i) pushing the substrate to the bottom of the trench by using asecond substrate, wherein the second substrate is selected from thegroup consisting of silicon, glass, polymer, stainless steel, metals,alloys, ceramics, semiconductors, dielectrics, and combinations andmodifications thereof and (ii) flipping the mold prior to the step oftransferring the shape, wherein the flipping results in the secondsurface facing the one or more microfabrication or etching sources,wherein the etching sources are selected from the group consisting ofions, etching gases, plasma, laser beams, and combinations ormodifications thereof. In one aspect the first substrate material isselected from the group consisting of a polymer, a rubber, a metal, asemiconductor, a dielectric, a mineral, a ceramic, and a glass. Inanother aspect the method further comprises the step of loading anactive agent supply in the device by a method selected from the groupconsisting of capillary action, dipping, injecting, and pressure loadingusing positive or negative pressures. In another aspect the one or moreactive agents comprise a solid, a liquid dosage, a semi-solid, a powder,or a hydrogel. In yet another aspect the device may optionally beattached to a medical device or a microelectronic circuit, wherein themicroelectronic circuit comprises at least one of a sensor, atransmitter, a receiver, a transceiver, a switch, a power supply or alight and the medical device is selected from the group consisting of astent, an urinary catheter, an intravascular catheter, a dialysis shunt,a wound drain tube, a skin suture, a vascular graft, an implantablemesh, an intraocular device, an eye buckle, a heart valve, andcombinations and modifications thereof.

In a specific aspects of the method described hereinabove the one ormore holes or perforations are circular with ranges from 1 nanometer-1centimeter, 100 nanometers-100 microns, 1 micron-50 microns, 10-30microns, 15-25 microns or 20 microns, the first substrate is a polymertube and the microfabrication technique is reactive ion etching using aplasma.

The method of the present invention may further comprise the optionalstep of polymer coating the device to prevent a release of the one ormore active agents until the coating is removed, which then causesrelease of the one or more active agents at a substantially constantrate, wherein the polymer coating is selected from the group consistingof polysaccharides, proteins, poly(ethylene glycol),poly(methacrylates), poly(ethylene-co-vinyl acetate), poly(DL-lactide),poly(glycolide), copolymers of lactide and glycolide, polyanhydridecopolymers, and combinations and modifications thereof. In other relatedaspects the one or more active agents are selected from the groupconsisting of drugs, proteins, vitamins, minerals, saccharides, lipids,nucleic acid, peptides, manure, plant nutrients, chemicals, perfumes,fragrances, flavoring agents, animal feed, effervescent gas releasingagents, and combinations and modifications thereof, wherein the drugsare selected from the group consisting of an analgesic agent, anantiinflammatory agent, an antihistaminic agent, an antiallergic agent,a central nervous system drug, an antipyretic agent, a respiratoryagent, a steroid, a local anesthetic, a sympathomimetic agent, anantihypertensive agent, an antipsychotic agent, a calcium antagonist, amuscle relaxant, a vitamin, a cholinergic agonist, an antidepressant, anantispasmodic agent, a mydriatic agent, an anti-diabetic agent, ananorectic agent, an antiulcerative agent, an anti-tumor agent, orcombinations modifications thereof, the proteins are selected from thegroup consisting of an immunoglobulin or fragments thereof, a hormone,an enzyme, a cytokine, a biomolecule, and combinations and modificationsthereof.

The device of the present invention is adapted for implantation,ingestion or placement in or on a living organism, attachment to themedical device, placement in soil, water or food, attachment to anaquarium feeder, and combinations and modifications thereof. In oneembodiment the method further includes steps for making the mold usedhereinabove, comprising the steps of: (i) providing a substratecomprising a first surface and a second surface, (ii) forming one ormore trenches on the first surface or on the second surface by one ormore microfabrication techniques, and (iii) forming one or more holes orperforations on the one or more trenches by one or more microfabricationtechniques. In one aspect the substrate comprises a material selectedfrom the group consisting of semiconductors, metals, dielectrics,polymers, rubbers, minerals, and ceramics. In related aspects the firstand the second surfaces can either be planar or non-planar surfaces.

In one aspect the one or more trenches are made by one or moremicrofabrication techniques selected from the group consisting ofphysical etching, chemical etching, reactive ion etching, physical vapordeposition, chemical vapor deposition, liftoff, electroplating,electroless plating, ion milling, laser ablation, plasma torch cutting,thin film deposition, lithography, mechanical drilling, sand blasting,and combinations and modifications thereof. In a specific aspect thesubstrate is a silicon wafer. In another aspect the one or moremicrofabrication techniques are selected from the group consisting ofthin film deposition, photolithography, wet anisotropic etching,reactive ion-etching, and combinations and modifications thereof.

In another embodiment the instant invention provides for a method formaking one or more trenches comprising the steps of: depositing at leastone layer on the first surface of the substrate, wherein the layer serveas etching mask layer, wherein the deposition is done by physical vapordeposition, coating a photo-resist layer onto the etching mask layer,creating a trench structure on the photo-resist layer by usingphotolithography, aligning a desired trench direction and creating oneor more alignment marks on the substrate, transferring the trenchstructure through the etching mask layer to the substrate or substratelayer by using one or more microfabrication techniques, and removing anyresidual substrate or substrate-layer materials from the formedtrenches. In related aspects the etching mask layer is selected from thegroup consisting of silicon dioxide, silicon nitride, chromium, nickel,aluminum, Al₂O₃, and combinations and modifications thereof, thephoto-resist layer is selected from the group consisting of Poly(methylmethacrylate) (PMMA), Poly(methyl glutarimide) (PMGI), Phenolformaldehyde resin, SU-8, and combinations and modifications thereof andthe microfabrication techniques are selected from the group consistingof photolithography, wet anisotropic etching, physical etching, chemicaletching, reactive ion etching, physical vapor deposition, chemical vapordeposition, liftoff, electroplating, electroless plating, ion milling,laser ablation, plasma torch cutting, thin film deposition, lithography,mechanical drilling, sand blasting, and combinations and modificationsthereof.

The method described hereinabove further comprises the additional stepof forming one or more holes or perforations on the one or more trenchescomprising the steps of: depositing at least one etching mask layer onthe second surface of the substrate or the substrate layer, defining awindow pattern by photolithography on the second surface of thesubstrate or the substrate layer, aligning the window pattern to thetrench on the first surface of the substrate or the substrate layerusing the one or more alignment marks, transferring the window patternonto the substrate or the substrate layer by a combination of reactiveion and wet anisotropic etching, defining the hole or perforationstructure by lithography, and forming the hole or the perforation byreactive ion etching. In one aspect the method further comprises thestep of hardening the mold structure. In one embodiment the presentinvention relates to a device for delivery of one or more active agentswith zero-order kinetics made by the method described hereinabove.

Yet another embodiment of the instant invention relates to a method formaking a device for delivery of one or more active agents withzero-order kinetics by a reactive ion etching technique comprising thesteps of: (i) providing a silicon-wafer mold comprising a first surfaceand a second surface, wherein the first surface comprises one or moretrenches, cavities or depressions, wherein each of the one or moretrenches, cavities or depressions comprise one or more holes,perforations or patterns, (ii) placing a first substrate in thetrenches, cavities or depressions, wherein the substrate may optionallybe held in place in the trench by using an adhesive, and (iii)transferring a shape of the holes, the perforations or the patterns inthe one or more trenches, cavities or depressions to the first substrateby using a reactive plasma to make the device for the delivery of theone or more active agents.

The method as described above further comprises the optional steps ofpushing the first substrate to the bottom of the trenches, cavities ordepressions by using a second substrate, wherein the second substrate isselected from the group consisting of silicon, glass, polymer, stainlesssteel, metals, alloys, ceramics, semiconductors, dielectrics, andcombinations and modifications thereof and of flipping the mold prior tothe step of transferring the shape, wherein the flipping results in thesecond surface facing the reactive plasma. In a specific aspect thefirst substrate is a planar or a non-planar substrate more specificallya cylindrical polymer tube of polyimide.

In one embodiment the silicon-wafer mold is made by a method comprisingthe steps of: providing the silicon-wafer substrate comprising a firstsurface and a second surface, forming one or more trenches on the firstsurface or on the second surface, and forming one or more holes,perforations or patterns on the one or more trenches. The step of makingthe one or more trenches further comprises the steps of: (i) depositingat least one etching mask layer on the silicon-wafer substrate by aphysical vapor deposition, wherein the etching mask layer comprises asilicon nitride layer and a chromium layer, (ii) spin-coating aphoto-resist layer onto the etching mask layer, (iii) creating a trenchstructure on the photo-resist layer by using a photolithographictechnique, (iv) aligning a desired trench direction and creating of oneor more alignment marks on the substrate, wherein the alignment marksare used to position the first substrate, (v) transferring the trenchstructure through the one or more etching mask layers to thesilicon-wafer substrate by the reactive ion etching technique using areactive plasma, and (vi) fabricating the trench structure by removal ofany residual substrate or substrate-layer materials from the formedtrenches by a wet anisotropic etching step.

The one or more one or more holes, perforations or patterns on the oneor more trenches are made by: (i) defining a window pattern by aphotolithographic technique aligned to the formed trenches on thesurface of the silicon-wafer not containing the formed trenchstructures, (ii) transferring the window pattern onto the trenchstructure by a combination of reactive ion etching and wet anisotropicetching, and (iii) forming one or more holes, perforations or patternson the one or more trenches by a combination of lithography and reactiveion etching. In related aspects the selection of the silicon-wafersubstrate is dependent on the shape of the trench structure to betransferred and the depth and the width of the trench structure isdependent on a geometry of the photo-resist layer and a duration of theanisotropic etching step. In another aspect the method comprises anoptional step of hardening the silicon-wafer mold by an application of asilicon-nitride layer to the surface. In one embodiment the presentinvention discloses a device for delivery of one or more active agentswith zero-order kinetics made by the method described above.

Yet another embodiment of the instant invention discloses a method formaking a device for delivery of one or more active agents withzero-order kinetics by a combination of photolithography and reactiveion etching techniques comprising the steps of: (i) providing a platformcomprising a first surface and a second surface, wherein the firstsurface comprises one or more trenches, cavities or depressions, whereineach of the one or more trenches, cavities or depressions comprise oneor more holes, perforations or patterns, (ii) placing a first substratein the trenches, cavities or depressions, wherein the substrate mayoptionally be held in place in the trench by using an adhesive (iii)depositing at least one masking layer on the platform and the firstsubstrate, (iv) depositing at least one photo-resist layer on the firstsubstrate, (v) defining one or more holes, perforations or patterns onthe photo-resist layer by lithography, (vi) performing a first reactiveion etching step using a reactive plasma to transfer the holes,perforations or patterns through the masking layer, and (vii) performinga second reactive ion etching step using the reactive plasma to transferthe holes, perforations or patterns through a wall of the firstsubstrate to form the device for delivery of one or more active agentswith zero-order kinetics. In specific aspects the first substrate is aplanar or a non-planar substrate and is a cylindrical polymer tube ofpolyimide. In one aspect a platform material is selected from the groupconsisting of a polymer, a rubber, a metal, a semiconductor, adielectric, a mineral, a ceramic, and a glass. In a specific aspect theplatform material is silicon. In another aspect a mask material isselected from the group consisting of a polymer, a rubber, a metal, asemiconductor, a dielectric, a mineral, a ceramic, and a glass. Inanother aspect the mask material is selected from the group consistingof chromium, aluminum, titanium, silicon dioxide, silicon nitride, anddiamond like glass. In yet another aspect the lithography is selectedfrom the group consisting of photolithography, imprint lithography,electron beam lithography, scanning probe lithography, nanospherelithography, and combinations and modifications thereof.

The silicon-wafer mold used in the method described above is made by aprocess comprising the steps of: (i) providing the silicon-wafersubstrate comprising a first surface and a second surface, (ii) formingone or more trenches on the first surface or on the second surface by amethod comprising the steps of: (a) depositing at least one etching masklayer on the silicon-wafer substrate; (b) spin-coating a photo-resistlayer onto the etching mask layer; (c) creating a trench structure onthe photo-resist layer by using a photolithographic technique; (d)aligning a desired trench direction and creating of one or morealignment marks on the substrate, wherein the alignment marks are usedto position the first substrate; (d) transferring the trench structurethrough the one or more etching mask layers to the silicon-wafersubstrate by the reactive ion etching technique using a reactive plasma,and (e) fabricating the trench structure by removal of any residualsubstrate or substrate-layer materials from the formed trenches by a wetanisotropic etching step.

In one aspect a selection of the silicon-wafer substrate is dependent onthe shape of the trench structure to be transferred. In another aspect adepth and a width of the trench structure is dependent on a geometry ofthe photo-resist layer and a duration of the anisotropic etching step.In yet another aspect the etching mask layer is a silicon nitride layer.In one embodiment the method provides a device for delivery of one ormore active agents with zero-order kinetics made by the method describedhereinabove.

In one embodiment the instant invention discloses a method for making acylindrical device for delivery of one or more active agents withzero-order kinetics comprising the steps of: providing a silicon wafermold comprising a first and a second surface, wherein the first surfacecomprises one or more cylindrical trenches, wherein the one or morecylindrical trenches comprise one or more circular holes orperforations, placing a polyimide tube in the trench, wherein the tubemay optionally be held in place in the trench by using an adhesive,performing an optional step of pushing the tube to the bottom of thetrench by using a substrate, and transferring the circular holes or theperforations in the one or more trenches to the polyimide tube byreactive ion etching using plasma to make the cylindrical device for thedelivery of the one or more active agents.

In one aspect the method further comprises the step of loading an activeagent supply in the delivery device by a method selected from the groupconsisting of capillary action, dipping, injecting, and pressure loadingusing positive or negative pressures. In another aspect the methodfurther comprises the optional step of flipping the silicon wafer priorto the step of transferring the circular holes, wherein the flippingresults in the second surface facing the etching sources, wherein theetching sources are selected from the group consisting of, ions, etchinggases, plasma, laser beams. In another aspect the one or more activeagents comprise a solid, a liquid dosage, a semi-solid, a powder or ahydrogel. In another aspect the device may optionally be attached to amedical device or a microelectronic circuit, wherein the microelectroniccircuit comprises at least one of a sensor, a transmitter, a receiver, atransceiver, a switch, a power supply, or a light. In yet another aspectthe circular holes or the perforations range from 1 nanometers-1centimeter, 100 nanometers-100 microns, 1 micron-50 microns, 10-30microns, 15-25 microns or 20 microns In another aspect the methodcomprises the optional step of polymer coating the device therebypreventing a release of the one or more active agents until the coatingis removed, which then causes release of the one or more active agentsat a substantially constant rate. In another aspect the one or moreactive agents are selected from the group consisting of drugs, proteins,vitamins, minerals, saccharides, lipids, nucleic acid, peptides, manure,plant nutrients, chemicals, perfumes, fragrances, flavoring agents,animal feed, effervescent gas releasing agents, and combinations andmodifications thereof. In one embodiment the present invention disclosesa cylindrical delivery device for one or more active agents made by themethod described above.

In another embodiment the present invention provides for a method fortreating a medical condition in a patient comprising the steps of:identifying the a patient exhibiting at least one symptom of the medicalcondition and implanting an impermeable therapeutic agent deliverydevice comprising a therapeutic agent supply capable of providing aneffective dose for the medical condition symptom, wherein the deliverydevice releases the therapeutic agent with zero-order kinetics. In oneaspect the medical condition is selected from the group consisting of acardiovascular disease, diabetes, epilepsy, Parkinson's disease, pain,cancer, ocular disease, and a fungal infection, wherein thecardiovascular disease is selected from the group consisting ofstenosis, restenosis, late stent thrombosis, stroke, myocardialinfarction, congestive heart disease, high blood pressure, angina,atherosclerosis or thrombosis. The diabetes is selected from the groupconsisting of type 1 diabetes, type 2 diabetes, juvenile diabetes, andgestational diabetes. The epilepsy is selected from the group consistingof generalized epilepsy, and partial epilepsy. The pain condition mayresult from an anatomical site selected from the group consisting ofabdomen, ankle, anal, back, bones, breast, ear, elbow, eye, finger,foot, groin, head, heel, hip, joints, knee, leg, muscles, neck, ribcage, shins, shoulder, flank, teeth, wrist or somatoform. The oculardisease comprises macular degeneration, glaucoma, uveitis, retinitis,corneal ulcer or endophthalmitis. The cancer is selected from the groupcomprising lung cancer, brain cancer, cervical cancer, uterine cancer,liver cancer, leukemia, Hodgkin's lymphoma, Non-Hodgkin's lymphoma,kidney cancer, ovarian cancer, skin cancer, testicular cancer, andthyroid cancer. The fungal infection comprises a toenail infection or afingernail infection.

In one aspect the therapeutic agent delivery device is made by themethod comprising the steps of: providing a mold comprising a firstsurface and a second surface, wherein the first surface comprises one ormore trenches, cavities or depressions, wherein a shape of the trench isselected from the group consisting of a cylinder, an oval, a cone, asphere, and a cuboid, wherein each of the one or more trenches compriseone or more holes or perforations, placing a first substrate in thetrench, wherein the substrate may optionally be held in place in thetrench by using an adhesive, and transferring a shape of the holes orthe perforations in the one or more trenches to the first substrate byone or more microfabrication techniques to make the device for thedelivery of the therapeutic agent. In another aspect the shape of theone or more holes or perforations is selected from the group consistingof a triangle, a polygon, an undecagon, a trapezium or trapezoid, aquadrilateral, an icosagon, a star polygon, an annulus, a circle, acrescent, an ellipse, an oval, an arbelos, a Reuleaux triangle, asemicircle, a sphere, an Archimedean spiral, an astroid, a deltoid, asuper ellipse, and a tomahawk.

The drug delivery device of the present invention is biodegradable andbioresorbable. The therapeutic agent supply comprises a pharmaceuticallyacceptable formulation. The drug delivery device comprises a surfacethat is configured for a controlled release of drug supply into ananatomical site, wherein the controlled release is maintained at asubstantially constant rate thereby resulting in zero-order kinetics.The device disclosed herein is capable of releasing drugs into a bodylumen for a time period ranging from days to several years, wherein therate and extent of release is dependent on the drug solubility,dimensions of the device and passageway, and density of drug(s) loadedinside the device. The drugs can be in a form selected from the groupcomprising a liquid form, a solid form, or any other form known in theart. In one embodiment, the drug comprises a class of thebiopharmaceutical classification system (BCS). In one embodiment, a BCSclass is selected from the group consisting of Class I (Highpermeability, High solubility); Class II (Low solubility, LowPermeability); Class III (High Solubility, Low Permeability); or ClassIV (Low solubility, Low permeability). The device of the presentinvention can comprise a single unit or a plurality of units.

DESCRIPTION OF THE DRAWINGS

A more complete understanding of embodiments of the disclosure will beapparent from the detailed description taken in conjunction with theaccompanying drawings in which:

FIG. 1 is a tubular drug delivery device having an inner lumen thatserves as drug reservoir and surface perforations that enable drugrelease from the device;

FIG. 2 is a cross-sectional view of the drug filled drug delivery devicein contact with an anatomical site;

FIG. 3 is a carrier, for example, a stent structure to which the drugdelivery device could be attached;

FIG. 4 is an example illustrating attachment of the drug delivery deviceto the carrier of FIG. 3;

FIG. 5 is a singular adhesive patch attached with several drug deliverytubes for combination therapy;

FIG. 6 is a graph illustrating cumulative zero order release of crystalviolet from three types of drug delivery device that differ in thenumber of surface perforations;

FIG. 7 is a graph illustrating cumulative percentage of crystal violetreleased from three types of drug delivery device that differ in thenumber of surface perforations;

FIG. 8 is a graph illustrating the linearity of drug release from thedrug delivery device in proportion to the number of holes;

FIG. 9 is a cumulative percentage of crystal violet released from oneopen end of the drug delivery device with no perforations;

FIG. 10 is a schematic of a mold showing the trenches and the throughholes;

FIGS. 11A-11D shows a process flow chart for fabricating a silicon mold;

FIG. 12A-12F illustrates one embodiment of a method for fabricating “U”or “V” shaped trenches on a silicon wafer. All images showcross-sectional views;

FIGS. 13A-13C shows a plain view of a silicon mold fabricated using theprocess shown in FIG. 11; FIG. 13A is the top side of the mold; FIG. 13Bis the backside of the mold; FIG. 13C is a single window structure;

FIGS. 13D-13E shows several steps to fabricate one embodiment of animpermeable therapeutic drug delivery device: FIG. 13D presents ascanning electron microscopic image of a “U” shaped trench pattern; FIG.13E presents an optical microscopic image of a circular passagewaythrough a polyimide tube made by photolithographic technique;

FIGS. 14A and 14B is a schematic of a process flow for etching holes ontubes with the help of a silicon mold;

FIGS. 15A-15E shows one embodiment of a schematic for the process flowfabricating micro-holes on a polymer tube. All images showcross-sectional views;

FIG. 16 is a stent structure whose struts can be built using theperforated drug delivery device;

FIG. 17 is drug delivery device in different sizes with no perforationsand only one end open for drug release;

FIG. 18 is a photograph of drug release via the perforations on the drugdelivery device into the dissolution medium;

FIG. 19 is a graph illustrating cumulative zero order release of crystalviolet from three types of drug delivery device of FIG. 17; and

FIG. 20 is a graph comparing the daily drug release from the drugdelivery devices of FIG. 17.

DESCRIPTION OF THE INVENTION

While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts thatcan be embodied in a wide variety of specific contexts. The specificembodiments discussed herein are merely illustrative of specific ways tomake and use the invention and do not delimit the scope of theinvention.

To facilitate the understanding of this invention, a number of terms aredefined below. Terms defined herein have meanings as commonly understoodby a person of ordinary skill in the areas relevant to the presentinvention. Terms such as “a”, “an” and “the” are not intended to referto only a singular entity, but include the general class of which aspecific example may be used for illustration. The terminology herein isused to describe specific embodiments of the invention, but their usagedoes not delimit the invention, except as outlined in the claims.

Before any embodiments of the invention are described in detail, it isto be understood that the invention is not limited in its application tothe details of construction and the arrangement of components set forthin the following description. The invention is capable of otherembodiments and of being practiced or of being carried out in variousways. Also it is to be understood that the phraseology and terminologyused herein is for the purpose of description and should not be regardedas limiting. The use of “including,” “comprising,” or “having” andvariations thereof herein is meant to encompass the items listedthereafter and equivalents thereof, as well as additional items.

As used herein the term “mold” refers to a solid support used to hold asubstrate or material and to transfer a shape to the substrate. Thesubstrate may have different desired shapes and sizes prior to beingplaced in the mold, or the mold may partially or completely reshape thesubstrate. The substrate is either placed, physically shaped, or pouredinto the mold to transfer a particular and/or contemplated opening,shape, structure or component by one or more techniques including butnot limited to lithography, imprinting, thermal and pressure molding,laser ablation, etching (e.g., reactive ion etching), ion milling, andother microfabrication techniques. The term includes both stationarymolds for processing a batch and moveable molds for continuous casting.

The term “therapeutic agent delivery device” or “unit” as used herein,refers to any device having a housing comprising an impermeable matrixmaterial encompassing a therapeutic agent filled hollow core. The devicemay be constructed such that the impermeable matrix material contains atleast one passageway capable of releasing the encompassed drug whereinthe ends of the device is plugged using a bioglue (i.e., for example, aalbumin-glutaraldehyde composition). Alternatively, the device may beconstructed such that the hollow core comprises an open end (i.e., forexample, an outlet port) wherein the housing is devoid of passageways.

The term “housing” as used herein, refers to any impermeable matrixmaterial, of any shape or size, encompassing a hollow core that iscapable of supporting the formation of at least one passageway. Forexample, the housing may be in the shape of a cylinder and comprise fromone to three passageways extending between the housing surface and theencompassed hollow core.

The term “hollow core” as used herein, refers to any open spaceencompassed by a housing, configured to contain a therapeutic agentsupply composition and/or formulation.

The term “passageway” or “channel’ as used herein, refers to any meansby which a drug molecule is transported from the hollow core, throughand out of the housing. Such means may include but are not limited to,an aperture, orifice, bore, channel outlet, or hole. The number and sizeof the “passageway” may be selected to tailor make the rate and extentof release of the agents. For example, the diameter of a passageway mayrange from several nanometers to several centimeters.

Preferably, the diameter of a passageway ranges between approximately 1nanometers-1 centimeter. More preferably, the diameter of a passagewayranges between approximately 100 nanometers-750 microns. Even morepreferably, the diameter of a passageway ranges between approximately 5microns (i.e., micrometers)-500 microns (i.e., micrometers). Preferably,the diameter of a passageway ranges between approximately 20 microns-100microns.

The term “outlet port” as used herein, refers to any open end of ahollow core.

The term “therapeutic agent” as used herein, refers to anypharmacologically active substance capable of being administered whichachieves a desired effect. Such agents can be synthetic or naturallyoccurring, non-peptide, proteins or peptides, oligonucleotides ornucleotides, polysaccharides or sugars.

The term “administered” or “administering” a therapeutic agent, as usedherein, refers to any method of providing an agent to a patient suchthat the agent has its intended effect on the patient. For example,administering may include but not limited to, local tissueadministration (i.e., for example, via a drug delivery device), oralingestion, transdermal patch, topical, inhalation, suppository etc.

The term “therapeutic agent supply” as used herein, refers to any drugdepot or reservoir in a form including, but not limited to, a solidcomposition, a hydrogel, a colloid, a suspension, solution, or powderthat is placed within a hollow core.

The term “drug” as used herein, refers to any therapeutically orprophylactically active agent, wherein the agent obtains a desireddiagnostic, physiological, or pharmacological effect. For example, adrug may include, but is not limited to, any compound, composition ofmatter, or mixture thereof that may be natural or synthetic, organic orinorganic molecule or mixture thereof which may be used as atherapeutic, prophylactic, or diagnostic agent. Some examples includebut are not limited to chemotherapeutic agents such as 5-fluorouracil,paclitaxel, sirolimus, adriamycin, and related compounds; antifungalagents such as fluconazole and related compounds; anti-viral agents suchas trisodium phosphomonoformate, trifluorothymidine, acyclovir andrelated compounds; cell transport/mobility impending agents such ascolchicine, vincristine, cytochalasin B and related compounds;antiglaucoma drugs such as beta blockers: timolol, betaxolol, atenolol,an related compounds; peptides and proteins such as insulin, growthhormones, insulin related growth factors, enzymes, and other compounds;steroids such as dexamethasone, prednisone, prednisolone, estradiol.ethinyl estradiol, and similar compounds; antihypertensives,anticonvulsants, blood glucose lowering agents, diuretics, painkillers,blood thinning agents, anesthetics, antibiotics, antihistaminics,immunosuppressants, anti-inflammatory agents, anti-oxidants, in vivodiagnostic agents (e.g., contrast agents), sugars, vitamins, toxinantidotes, and molecules developed by gene therapy.

The term “bodily fluid” as used herein refers to any liquid-like orsemi-solid composition derived from an organism including but notlimited to blood, serum, urine, gastric, and digestive juices, tears,saliva, stool, semen, and interstitial fluids derived from tumoredtissues.

The term “analyte” as used herein, refers to any compound within a bodyfluid including, but not limited to, a small organic molecule, amineral, an inorganic ion, a protein, or a hormone.

The term “biopharmaceutical classification system” or “BCS” as usedherein, refers to a scientific classification framework for drugsubstances based on their aqueous solubility and intestinal permeability(US Dept. Health & Human Services, Food and Drug Administration Centerfor Drug Evaluation and Research (CDER) August 2000).

The term “permeability” as used herein, refers to any material thatpermits liquids or gases to pass through. The term “impermeable” as usedherein, refers to any material that does not permit liquids or gases topass through.

The term “solubility” as used herein, refers to the amount of asubstance that will dissolve in a given amount of another substance.Typically solubility is expressed as the number of parts by weightdissolved by 100 parts of solvent at a specified temperature andpressure or as percent by weight or by volume.

The term “controlled release” as used herein, refers to a predictabledissolution of a therapeutic agent supply that may be described bymathematical relationships. For example, a controlled release may followzero order kinetics.

The term “zero-order kinetics” as used herein, refers to a constantcontrolled release of a therapeutic agent wherein the release rate thatdoes not change during the dissolution of a therapeutic drug supply(i.e., the release rate maintains linearity throughout the dissolutionof the drug supply).

The term “substantially constant rate” as used herein, refers to a zeroorder kinetic release of a therapeutic agent wherein a regressioncoefficient is at least 0.90 (i.e., for example, R²)

The term “long-term administration” as used herein, refers to anytherapeutic agent that is given to a patient or subject at greater thana single dose equivalent. For example, such administration may comprisemultiple doses on a single day or a single dose over several days.Alternatively, such administration may comprise a continuoussubstantially constant rate over the time period comprising hours, days,week or years.

The term “geometrical shape” as used herein, refers to any customdesigned composition that is formulated for implantation into a specificanatomical site of a biological organism. For example, such compositionsmay include but are not limited to, a cuboid, a cube, a sphere, a cone,an oval, or a cylinder. In particular, a cube is shaped having six sidesof equal area whereas a cuboid in the broadest sense includes, but isnot limited to, polygonal, rhombus, trapezoid, rectangular, and squarecross-sectional shapes with substantially squared or rounded corners andwith perpendicular or angled sides.

The term “loading” or “loaded” as used herein, refers to the placementof a therapeutic agent supply within the hollow core of a drug deliverydevice. On the other hand, a device may be provided that is “preloaded”with a therapeutic agent supply,

The term “body lumen” as used herein, refers to any cavity of a tubularbody organ (i.e., for example, the interior of a blood vessel).

The term “biocompatible” as used herein, refers to any material does notelicit a substantial detrimental response in the host. There is alwaysconcern, when a foreign object is introduced into a living body, thatthe object will induce an immune reaction, such as an inflammatoryresponse that will have negative effects on the host. In the context ofthis invention, biocompatibility is evaluated according to theapplication for which it was designed: for example; an implanted medicaldevice (i.e., for example, an impermeable therapeutic agent deliverydevice) is regarded as biocompatible with the internal tissues of thebody. Preferably, biocompatible materials include, but are not limitedto, biodegradable and biostable materials.

The term “biodegradable” as used herein, refers to any material that canbe acted upon biochemically by living cells or organisms, or processesthereof, including water, and broken down into lower molecular weightproducts such that the molecular structure has been altered.

The term “bioresabsorbable” as used herein, refers to any material thatis assimilated into or across bodily tissues. The bioresorption processmay utilize both biodegradation and/or bioerosin.

The term “non-biodegradable” as used herein, refers to any material thatcannot be acted upon biochemically by living cells or organisms, orprocesses thereof, including water

The term “non-bioreabsorbable” as used herein, refers to any materialthat cannot be assimilated into or across bodily tissues. The term“medical device” as used herein, refers broadly to any apparatus used inrelation to a medical procedure and/or therapy. Specifically, anyapparatus that contacts a patient during and/or after a medicalprocedure or therapy is contemplated herein as a medical device.Similarly, any apparatus that administers a compound or drug to apatient during or after a medical procedure and/or therapy iscontemplated herein as a medical device. Such devices are usuallyimplanted and may include, but are not limited to, urinary andintravascular catheters, dialysis shunts, wound drain tubes, skinsutures, vascular grafts and implantable meshes, intraocular devices,implantable drug delivery systems (i.e., for example, a stent or eyebuckle) and heart valves, and the like. A medical device is “coated”when a medium (i.e., for example a polymer) comprising a therapeuticagent becomes attached to the surface of the medical device. Thisattachment may be permanent or temporary. When temporary, the attachmentmay result in a controlled release of a drug.

The term “attached” as used herein, refers to any interaction between amedium (or carrier) and a drug. Attachment may be reversible orirreversible. Such attachment includes, but is not limited to, covalentbonding, ionic bonding, Van der Waals forces or friction, and the like.A drug is attached to a medium (or carrier) if it is impregnated,incorporated, coated, in suspension with, in solution with, mixed with,etc.

The term “anatomical site” as used herein refers to any internal orexternal, deep or superficial body cavity, lumen, tissue, or organ of amammalian organism. Some examples of anatomical sites where the medicaldevice can be placed includes, but is not limited to, eyes, toenails,fingernails, epidermis (i.e., for example, skin), nasal cavity, gastrointestinal tract, valves, veins, and arteries such as coronary arteries,renal arteries, aorta, cerebral arteries, including for example, acerebral arterial wall.

The terms “reduce,” “inhibit,” “diminish,” “suppress,” “decrease,”“prevent” and grammatical equivalents (including “lower,” “smaller,”etc.) when in reference to the expression of any symptom in an untreatedpatient relative to a treated patient, mean that the quantity and/ormagnitude of the symptoms in the treated patient is lower than in theuntreated patient by any amount that is recognized as clinicallyrelevant by any medically trained personnel. In one embodiment, thequantity and/or magnitude of the symptoms in the treated patient is atleast 10% lower than, preferably, at least 25% lower than, morepreferably at least 50% lower than, still more preferably at least 75%lower than, and/or most preferably at least 90% lower than the quantityand/or magnitude of the symptoms in the untreated patient.

The term “patient”, as used herein, is a human or animal and need not behospitalized. For example, out-patients, persons in nursing homes are“patients.” A patient may comprise any age of a human or non-humananimal and therefore includes both adult and juveniles (i.e., children).It is not intended that the term “patient” connote a need for medicaltreatment, therefore, a patient may voluntarily or involuntarily be partof experimentation whether clinical or in support of basic sciencestudies.

The term “effective amount” as used herein, refers to a particularamount of a pharmaceutical composition comprising a therapeutic agentthat achieves a clinically beneficial result (i.e., for example, areduction of symptoms). Toxicity and therapeutic efficacy of suchcompositions can be determined by standard pharmaceutical procedures incell cultures or experimental animals, e.g., for determining the LD₅₀(the dose lethal to 50% of the population) and the ED₅₀ (the dosetherapeutically effective in 50% of the population). The dose ratiobetween toxic and therapeutic effects is the therapeutic index, and itcan be expressed as the ratio LD₅₀/ED₅₀. Compounds that exhibit largetherapeutic indices are preferred. The data obtained from these cellculture assays and additional animal studies can be used in formulatinga range of dosage for human use. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with little or no toxicity. The dosage varies within this rangedepending upon the dosage form employed, sensitivity of the patient, andthe route of administration.

The term “derived from” as used herein, refers to the source of acompound or sequence. In one respect, a compound or sequence may bederived from an organism or particular species. In another respect, acompound or sequence may be derived from a larger complex or sequence.

The term “pharmaceutically” or “pharmacologically acceptable”, as usedherein, refer to molecular entities and compositions that for use inhumans and other mammals that have been approved by a drug and medicaldevice regulating authority or are under clinical development and haveacceptable risk to benefit ratio.

The term, “pharmaceutically acceptable carrier”, as used herein,includes any and all solvents, or a dispersion medium including, but notlimited to, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetable oils, coatings, isotonic and absorption delayingagents, liposome, commercially available cleansers, and the like.Supplementary bioactive ingredients also can be incorporated into suchcarriers.

The term “formulation” as used herein, refers to any compositioncomprising a therapeutic agent intended for administration to a patientand/or subject. For example, a formulation may include, but not belimited to, a solid, a powder, a semisolid, or a gel.

This invention relates to methods of making a therapeutic agent deliverydevice which is capable of delivering a diagnostic, therapeutic, and/orprophylactic agent to a desired targeted site. Optionally, the deliverydevice may monitor bodily fluid analytes. Additionally, the methodcreates a device that can provide for the release of the agent from thedevice is unidirectional and at a controlled desirable rate. Forexample, the agent may include, but is not limited to, drugs, proteins,peptides, biomarkers, bioanalytes, and/or genetic material.

Miniature substrates, such as polymer micro-tubes, are findingincreasing industrial and bio-medical applications. In many cases, theminiature substrates need further processing to fabricate specificstructures to complete the desired devices. One example is to fabricatemicro-holes on the surfaces of polymer tubes to form flexible drugrelease devices.

The method of laser ablation is commonly used to fabricate micro-holeson polymer tubes. It is a fast one-step process without using chemicals.However, the fabrication process is serial where the holes are made oneby one limiting it to a low throughput manufacturing. For certainapplications, a single device may require a large number of micro-holeson a tube. In this case, the manufacturing cost would be very high ifthe sequential laser ablation method is used.

To overcome the disadvantages of laser ablation, the present inventiondiscloses a technology based on parallel processing to fabricatemicro-holes on tubes employing lithography and reactive ion etchingtechniques. Such a parallel processing method is fast and low-cost andis well suited for mass production. In addition, the method has thepotential to integrate electrical or electronic sensors and devices tocontrol the drug delivery devices. However, the photo-resist and maskingmaterial used in the fabrication process may contaminate the tubes. Thebaking step used in photo-lithography and the chemicals used to cleanthe tubes after etching may change the properties of the polymer aswell. It would be difficult to use this method to fabricate devicestructure using chemically unstable polymeric materials, e.g.,bio-degradable tubes. Furthermore, due to the nonplanar surface of thetubes, the mask used for lithographic patterning may not protect tubeswell during the etching process. As a result, cracks can develop on thetube surface, reducing the manufacturing yield. Since the method isbased on a multi-step process: mask film deposition, photo-lithography,etching etc. to fabricate the device, an extensive facility equippedwith the proper manufacturing tools is required, making themanufacturing method expensive.

The present invention discloses another method which retains theefficient approach of parallel processing but incorporates a simplemolding method to form the micro-holes on flexible polymer tubes,including bio-degradable tubes. The process is fast, efficient, and lowcost.

Although it is not necessary to understand the mechanism of aninvention, it is believed that such a delivery device will eliminate theneed for repeated dosing of a medicament thereby improving patientcompliance. It is further believed that such a device would alsodecrease patient side effect risk, prolonged and unnecessary pain, andexpense for many long term therapeutic regimens.

The instant invention uses a mold to fabricate micro-structures onminiature substrates such as micro-tubes. Trenches on the mold can holdtubes for convenient handling. The mold also has predefinedconfigurations of through hole structures from the backside. Thesepredefined through hole structures can be transferred to the desiredpositions on tubes in a single step of etching without any alignment andfurther manipulation. The mold can be reused for many batches. It ismore efficient than laser ablation because it can process many tubes andfabricate many structures simultaneously. The process is simple and runsin a parallel manner. It is simpler than the micro-fabrication techniquedisclosed in U.S. Provisional Patent No. 61/225,352 because it requiresno expensive processing steps, such as lithography, multiple thin filmdeposition and etching.

This invention simplifies significantly the process to fabricatemicrostructures on miniature substrates such as micro-tubes. Once themold is formed, the fabrication process can be done in a single step.Except the parts exposed to the through holes of the mold, tubes underprocessing is intact. So the tubes are free of etching-induced cracks.Because it is a chemical-free process, it avoids any possible chemicalcontamination. It can also be easily applied to chemically unstablematerials, e.g., bio-degradable tubes which are difficult to process byconventional micro-fabrication techniques without degrading the materialproperties of the tubes.

The disclosed invention combines the advantages of both laser ablationand micro-fabrication. Compared to laser ablation which is a serialprocess, the parallel nature of the present method enables a fastthroughput thus reduces the manufacturing cost for mass production. Thepredefined structures on the mold make it free from any alignments andcomplex optics manipulating. Compared to the micro-fabrication techniquedisclosed in U.S. Provisional Patent No. 61/225,352 which is amulti-step process, it is a single-step process. This greatly shortensthe manufacturing time and reduces both the material cost and investmenton capital equipment. This crack-free process also improves the yield.Furthermore, the topside of the mold can also work as a template similarto the one in U.S. Provisional Patent No. 61/225,352. In another word,both sides of a tube can be processed by the mold technology disclosedherein. The polymer tubes or other substrates where the micro-holes areformed on can be integrated with microelectronics circuits and MEMSstructures to form integrated devices for monitoring and controlledrelease of chemical agents or medications.

The present invention offers several advantages over existing drugdelivery devices. One such advantage is to achieve zero order releasekinetics without an initial burst effect such as is found in currentdesigns that are known in the art. In its most basic form, the inventionrelates to a medical device which acts as a housing containing drugreservoir, and means for facilitating release of drug from the drugreservoir to an anatomical site. The device enables a mechanism in whichthe drug is released at equal increments from the reservoir per unittime.

One feature of the invention comprises simplicity of design andprolonged duration drug release capability up to, and including, severalyears. Further, drug release may be unidirectional is not subject toback transfer or build up of the drug as long as sink conditions aremaintained. Although it is not necessary to understand the mechanism ofan invention, it is believed that such a delivery device will eliminatethe need for repeated dosing of a medicament thereby improving patientcompliance. It is further believed that such a device would alsodecrease patient side effect risk, prolonged and unnecessary pain, andexpense for many long term therapeutic regimens. In any drug treatment,it is desired to deliver a pharmaceutical agent directly at the targetedsite for a sufficient duration in order to produce a required beneficialeffect. Since the advent of time, man has sought means to find bettercure. Oral, topical and inhalation are commonly used modes of drugadministration. Modern era has witnessed development of alternate routessuch as, systemic, intravitreal, and pulmonary delivery of drugs.However, age problems and disadvantages are associated with theseconventional methods that restrict their effectiveness.

In most instances, drugs administered via these conventional routesresult in the appearance of various deleterious side effects. Forexample, some drugs that are administered orally may not be properlyabsorbed through the stomach wall; may be degraded by thegastrointestinal tract; or may irritate the stomach causing an unwantedside effect. For example, insulin, which is a protein based drug, cannotbe given orally since it would be degraded by proteolytic enzymes andtherefore, must be given by injection. Further, Intravenous Ganciclovir(GCV) is effective in treatment of cytomegalovirus (CMV) retinitis inAIDS patients but 30-50% patients experience bone marrow toxicityresulting in neutropenia (neutrophil count<1000). Although anintravitreal administration of 200-400 μg/day of GCV twice a week hasdecreased the instances of neutropenia, this regimen requires repeateddosing thereby causing extreme discomfort to patients.

Some conventional routes of administration are problematic inmaintaining a constant therapeutic level. For example, a drugconcentration may either reach a toxic level or alternatively it maydecrease as the drug is either metabolized (i.e., for example, by theliver) or eliminated (i.e., for example, by the kidney). Frequently, thedrug levels may drop below the therapeutic levels and a second dose isneeded.

One way to overcome this problem is to deliver drugs locally, that is,directly at the desired physiological site. A number of implantable drugdelivery devices have been suggested to be capable of delivering a drugto a body lumen. One advantage of implanted drug delivery devices isrelated to local administration of a drug. Although it is not necessaryto understand the mechanism of an invention, it is believed that localadministration inherently improves efficacy and decreases side effects,as compared to other routes of administration such as oral, rectal,topical, or systemic. Nonetheless, one problem with the knownimplantable drug delivery devices is that the delivery rate cannot becontrolled during all operational phases of the devices (i.e., forexample, drug delivery rates may change thereby resulting in first orderdelivery kinetics or second order delivery kinetics).

Such problems result in a drug delivery device that administers drugs inan unpredictable pattern, thereby resulting in poor therapeutic benefit.For example, one popular drug delivery device is a drug eluting stent.Stents are mesh-like steel or plastic tubes that are used to open up aclogged atherosclerotic coronary artery or a blood vessel undergoingstenosis. A drug may be attached onto, or impregnated into, the stentthat is believed to prevent re-clogging or restenosis a blood vessel.However, the initial release of the drug from a stent may be very rapid,thereby releasing 20-40% of the total drug in a single day. Such highconcentrations of the drug have been reported to result in cytotoxicityat the targeted site. To maintain constant levels, a drug should bereleased from the delivery system at a rate which does not change withtime (i.e., for example, zero order kinetics). In many systems however,the release rate is proportional to time (i.e., first order) or thesquare root of time (sometimes referred to as Fickian release kinetics).

A zero order drug controlled release system offers many advantages: i)Drug levels are continuously maintained at a desirable therapeuticrange; ii) Adverse effects are reduced by targeting delivery to aspecific site and avoiding distribution to unwanted tissues; iii) Doseof drug is decreased while mean residence time is increased; iv) Numberof doses is decreased; v) Less invasive dosing decreases patient traumaand improves patient compliance; and vi) An inert and impermeable deviceprotects the drug in the hostile environment.

Several implantable drug delivery systems have been reported which arecapable of administering drugs at zero order rates. One of the earliestzero order devices was developed as an ocular insert as described inU.S. Pat. No. 3,618,604. The device was described as a sealed containerhaving the drug in an anterior chamber. The device was capable ofcontinuously releasing pilocarpine at a predetermined rate of 20-40μg/hour for seven days for treating glaucoma. The ocular pressure leveland pupil diameter were maintained throughout the 24-hour period ofOcusert placement. Nonetheless, as described in U.S. Pat. No. 4,014,335certain problems have been identified with such devices such as thedifficulty in sealing the margins to form a container. In addition,stresses and strains introduced into the membrane walls from deformationduring manufacturing of the devices may cause the reservoir to ruptureand leak.

Another such device, as described in U.S. Pat. No. 5,660,848 comprise asubdermal implant for uses as a contraceptive. This device was describedas a central drug core; an intermediate polymeric layer controlling therate of diffusion of drug; and the outer polymeric layer extendingoutwards from the intermediate layer. The device described in U.S. Pat.No. 5,660,848 does have problems. For example, the macroscopic size ofthe device releases significant amounts of the drug, progesterone, intothe circulation causing problems of weight gain and vision loss in asmall percentage of treated patients.

Osmotic minipumps have been reported as capable of providing zero-orderdrug release. One such device as described in U.S. Pat. No. 3,993,073has a reservoir, which is formed of a drug carrier permeable to thepassage of the drug and in which the drug has limited solubility. Thewall is formed in at least a part of a drug release rate controllingmaterial also permeable to the passage of the drug, but the rate ofpassage of the drug through the wall is lower than the rate passage ofthe drug through the drug carrier so that drug release by the wall isthe drug release rate controlling step for releasing drug from the drugdelivery device. Most of the osmotic pump devices are developed in formof a tablet or capsule, which can deliver drug up to a few hours or daysand are not suitable for diseased conditions wherein, a constant amountof drug needs to be delivered for months and/or years.

Another minipump device, as described in U.S. Pat. Nos. 6,217,895 and6,375,972B1 comprises a sustained release device for the eye. Thisdevice is described as an inner core or reservoir including an effectiveagent; an impermeable tube which encloses the reservoir, at three sides;and a permeable membrane at the fourth side through which drug releasetakes place. The device is few hundred microns in dimensions andproduces linear release. However, one drawback of the membrane basedreservoir system is that the choice of the membrane is restricted by thesolubility and diffusion coefficient of the drug. Consequently, adifferent membrane is required for each drug.

The problem of device size is extremely important in the design ofdevices as it dictates the variety of anatomical sites where it can beplaced. A macro-sized device may be suitable for implantation in or nearvertebrae but it may not be suitable for placement in an eye. Largerdevices may also involve complex surgery both during implantation andremoval. Furthermore, a larger device may also result in longer healingand recovery periods or device rejection by the body. Over the years,the dimensions of implantable drug delivery devices have decreased andthe duration of release has increased. These reductions in size hasimproved immunological responses, biocompatibility, and reduced sideeffects associated with earlier devices. Hence, there remains a need fordrug delivery device which can be optimized to deliver any therapeutic,diagnostic, or prophylactic agent for any time period up to severalyears maintaining a controlled and desired rate.

In some embodiment, the present invention contemplates methods anddevices which comprise an injectable and/or implantable medical devicehaving at least one orifice on the surface. Although it is not necessaryto understand the mechanism of an invention, it is believed that thedevices can be used to obtain a desired local or systemic physiologicalor pharmacological effect in mammals, e.g., humans. In one embodiment,the device comprises a hollow matrix of any size or shape, which can bemade from materials including, but not limited to, metals and/or nonmetals. In one embodiment, the device comprises a reservoir capable ofreleasing at least one therapeutic, diagnostic, and/or prophylacticagent via the orifices to the desired anatomical site. In oneembodiment, a perforated matrix can either be used individually, or as aset, which in turn can be either built as part of a device or mounted ona medical device, including, but not limited to, a stent. Although it isnot necessary to understand the mechanism of an invention, it isbelieved that the presently contemplated device, due to its compositestructure, has an ability to combine several release mechanisms, leadingto controllable zero-order release kinetics. For example, such drugrelease may be dependent on factors including, but not limited to, drugsolubility, dimensions of the matrix and orifice, and/or density ofdrug(s) loaded inside the device. It is further believed that, thecomposition provides zero-order kinetics, in part, because the diffusionrate of the drug from the device is slow which enables sink conditions.Hence, no back transfer or build up of drug occurs at anytime. Polymersare not required for controlled release.

I. Drug Release Kinetics: Over recent years, drug release/dissolutionfrom solid pharmaceutical dosage forms has been of increasing interest.For example, whenever a new solid dosage form is developed or produced,drug dissolution studies are performed to determine the releasecharacteristics (i.e., for example, kinetics) of the formulation.Sometimes, mathematic models are derived from a theoretical analysis ofthe observed kinetics. Usually, however, a theoretical concept is notapplicable and empirical equations are applied instead. For example,drug dissolution from solid dosage forms has been described by kineticmodels in which the dissolved amount of drug (Q) is a function of thetest time, t or Q=f (t). Some analytical definitions of the Q(t)function are commonly used, including, but not limited to, zero-order,first-order, Hixson-Crowell, Weibull, Higuchi, Baker-Lonsdale,Korsmeyer-Peppas and Hopfenberg models. Other release parameters, suchas dissolution time (tx %), assay time (tx min), dissolution efficacy(ED), difference factor (f1), similarity factor (f2) and Rescigno index(xi1 and xi2) can be used to characterize drug dissolution/releaseprofiles.

Much effort has been expended to develop zero-order drug releasekinetics for various pharmaceutical drug formulations. Some having skillin the art believe that linear drug release provides a more stabletherapeutic drug level over time and therefore provides a morepredictable clinical response. Ideal drug delivery process would,therefore, be expected to exhibit zero-order kinetics. However, inpractice, most conventional drug delivery processes follow first-orderkinetics. Nonetheless, some mathematical models have determined thatcertain polymer shapes of drug micro-carriers that may support nearzero-order release. Such mathematical models may be derived from theCarslaw and Jaeger equation of conduction of heat that models therelationship between carrier geometry shape and drug concentration. Ithas been suggested that by reducing the k value (i.e., for example, aratio of volume of the fluid to that of the sphere) gives a nearzero-order kinetics drug delivery response for most micro carriergeometry shapes that are roughly spherical in shape. On the other hand,tetrahedron shapes exhibits the best mathematical fit and tabletsexhibit the worst mathematical fit. Ng et al., “Optimization ofNanoparticle Drug Micro Carrier on the Pharmacokinetics of Drug Release:A Preliminary Study” J Med Syst. 32:85-92 (2008).

Nonetheless, a tablet formulation with a zero-order drug release profilehas been reported that is based on a balanced blend of three matrixingredients. Specifically, matrices comprising Polyox®, Carbopol®, andlactose were evaluated for their effect on the release rate oftheophylline. The tablets were prepared by direct compression and weresubjected to an in vitro dissolution study. A balanced blend of thesematrix ingredients could be used to attain a zero-order release profile.El-Malah et al., “D-Optimal Mixture Design: Optimization of TernaryMatrix Blends for Controlled Zero-Order Drug Release from Oral DosageForms” Drug Dev Ind Pharm. 32:1207-18 (2006). Other polymer basedmatrices have been produced that support zero-order delivery of thehighly soluble drug alfuzosin hydrochloride. These matrices werereported to contain polyethylene oxide (PEO),hydroxypropylmethylcellulose (HPMC), sodium bicarbonate, citric acid andpolyvinyl pyrrolidone. These drug release kinetics, matrix swelling andsubsequent erosion during dissolution was suggested as suitable for agastro-retentive drug delivery system in the proximal small intestine.Liu et al., “Zero-Order Delivery of a Highly Soluble, Low Dose DrugAlfuzosin Hydrochloride Via Gastro-Retentive System” Int J Pharm348:27-34 (2008).

Zero-order extended release formulations have also been reported. Forexample, a gliclazide extended-release formulation was created using twohydrophilic polymers: HPMC K 15M and sodium alginate as retardant.Further, the effects of HPMC, lactose, and sodium alginateconcentrations were studied for their effects on the gliclazide releaserate. The drug release percent at 3, 6, 9 and 12 h were restricted to20-30, 45-55, 70-80 and 90-100%, respectively. The mechanism of drugrelease from these extended-release matrix tablets was followed by azero-order release pattern. Jin et al., “Optimization of ExtendedZero-Order Release Gliclazide Tablets Using D-Optimal Mixture Design”Yakugaku Zasshi 128:1475-1483 (2008). An alternative extended releasegliclazide tablet formulation was tested that had a central compositedesign with pH-dependent matrix forming polymers keltone-HVCR andeudragit-EPO. These tablets were evaluated for hardness, percent drugrelease after 1 hr, percent drug release after 6 hr, diffusion exponentand time required for 50% of drug release. One formulation, containing 8mg of keltone-HVCR and 14.10 mg of eudragit-EPO, provides a sufficienthardness (>4.5 kg/cm2) and exhibited zero-order release properties.Vijayalakshmi et al., “Development of Extended Zero-Order ReleaseGliclazide Tablets by Central Composite Design” Drug Dev Ind Pharm.34:33-45 (2008). Glipizide hydrophilic sustained-release matrices havealso been evaluated for in vitro-in vivo correlations (IVIVC) in thepresence of a range of formulation/manufacturing changes. The effect ofpolymeric blends of ethyl cellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, xanthan gum, guar gum, Starch 1500, andlactose on in vitro release profiles were studied and fitted to variousrelease kinetics models. An IVIVC was established by comparing thepharmacokinetic parameters of M-24 and Glytop-2.5 SR formulations aftersingle oral dose studies on white albino rabbits. The matrix M-19(xanthan:MCC PH301 at 70:40) and M-24 (xanthan:HPMC K4M:Starch 1500 at70:25:15) showed zero-order glipizide release. A Kopcha model analysisrevealed that the xanthan gum has a determinative effect on thezero-order release profile. These data suggest that proper selection ofrate-controlling polymers with release rate modifier excipients maydetermine overall release profile, duration and mechanism from directlycompressed matrices. Sankalia et al., “Drug Release and SwellingKinetics of Directly Compressed Glipizide Sustained-Release Matrices:Establishment of Level A IVIVC” J Control Release 129:49-58 (2008).

Osmotic minipumps have been reported as capable of providing zero-orderdrug release. For example, a monolithic osmotic pump tablet system(MOTS) containing isosorbide-5-mononitrate (5-ISMN) was evaluated forvariations in tablet formulations such as, size and location of thedelivery orifice, membrane variables, and pH value of the dissolutionmedium on 5-ISMN release from MOTS. These results demonstrated that thetablet core played a role in MOTS function, and membrane variables couldalso affect the 5-ISMN release rate. The optimal formulation of 5-ISMNMOTS was determined by a uniform design. Furthermore, the logpharmacokinetics and relative bioavailability of the test formulation(5-ISMN MOTS) have been compared with the reference formulation (Imdur®:60 mg/tablet, a sustained release, SR, tablet system) following an oralsingle dose of 60 mg given to each of six Beagle dogs. The mean drugfraction absorbed by each dog was calculated by the Wagner-Nelsontechnique. The results showed that drug concentration in plasma could bemaintained more stable and longer after the administration of 5-ISMNMOTS as compared with the matrix tablets of Imdur®, and a level A “invitro/in vivo correlation” was observed between the percentage releasedin vitro and percentage absorbed in vivo. It was concluded that 5-ISMNMOTS is more feasible for a long-acting preparation than 5-ISMN SRtablet system as once-a-day treatment, and it is very simple inpreparation, and can release 5-ISMN at the rate of approximately zeroorder for the combination of hydroxypropyl-methyl cellulose as retardantand NaCl as osmogent. Duan et al., “Development of Monolithic OsmoticPump Tablet System for Isosorbide-5-Mononitrate Delivery and Evaluationof it In Vitro and In Vivo” Drug Dev Ind Pharm 31:1-9 (2008).Nonetheless, osmotic minipumps rely upon passage of analytes acrosssemipermeable membranes that encompass a drug solution. Consequently,osmotic minipumps do not support zero order release kinetics usingimpermeable housing matrix materials.

II. Impermeable Drug Delivery Devices: Some embodiments of the presentinvention offer several advantages over existing drug delivery devices.One such advantage is to achieve stable zero order release kineticswithout an initial burst effect such as is found in previously reporteddevices (supra). Although it is not necessary to understand themechanism of an invention, it is believed that an impermeable housingencompassing a therapeutic agent supply plays a role in providing stablezero order release kinetics. Although it is not necessary to understandthe mechanism of an invention, it is believed that a compositioncomprising a solid therapeutic agent supply plays a role in providingstable zero order release kinetics.

In one embodiment, the present invention contemplates a medical devicecomprising an impermeable housing encompassing a therapeutic agent(i.e., for example, a drug) supply (i.e., for example, a reservoir ordepot). Some embodiments may also comprise at least one passageway oroutlet port, thereby facilitating release of drug from the drugreservoir to an anatomical site. The device enables a mechanism in whichthe drug is released from the reservoir at equal increments per unittime (i.e., for example, a stable controlled desired release rate and/orzero order release kinetics). This capability allows embodiment of thepresent invention to release drugs for prolonged durations extendingfrom several hours to several years.

Thus, the presently contemplated device presents an improved medicaldevice which maintains its physical and chemical integrity in both theenvironments of use and in the presence of agent during the controlledand continuous dispensing of agent over a prolonged period of time.Additionally, due to composite design of the device, there is no need ofany coating or polymers for controlled release of agents.

In one embodiment, the device may comprise a single housing, wherein thehousing encompasses an agent supply comprising at least two therapeuticagents. In one embodiment, the device releases a first drug at a firstrelease rate. In one embodiment, the device releases a second drug at asecond release rate. Although it is not necessary to understand themechanism of an invention, it is believed that the first and secondagents are released at different rates because of differentialsolubility relative to the agent supply.

In one embodiment, the device may comprise at least two housings. In oneembodiment, the first housing comprises large diameter passageways. Inone embodiment, the second housing comprises small diameter passageways.In one embodiment, the first housing encompasses a first agent supplythat is released at a first rate. In one embodiment, the second housingencompasses a second agent supply that is released at a second rate.Although it is not necessary to understand the mechanism of aninvention, it is believed that the first agent is released at a fasterrate than the second agent.

A. The Impermeable Housing: In some embodiments, the device housingcomprises an impermeable composition, thereby providing unidirectionalrelease. Although it is not necessary to understand the mechanism of aninvention, it is believed that as long as the therapeutic agent supplydoes not disintegrate (i.e., for example, “sink conditions” aremaintained), the device agent release function will not be compromisedby agent back-transfer or build up of the agent within the passagewaysand/or outlet port.

The impermeable housing that encompasses a therapeutic agent supply withwhich the delivery device is made includes, but is not limited to,naturally occurring or synthetic materials that are biologicallycompatible with body fluids and tissues and are essentially insolubleand impermeable to the body fluid with which it will come in contactwith. For example, these materials include, but are not limited to,glass, metal, ceramics, minerals, and polymers such as polyimides,polyamides, polyvinyl acetate, crosslinked polyvinyl alcohol,cross-linked polyvinyl butyrate, ethylene ethylacrylate, copolymer,polyethyl hexylacrylate, polyvinyl chloride, natural rubber, Teflon®,plastisized soft nylon, and silicone rubbers.

In one embodiment, the present invention contemplates a compositioncomprising a therapeutic agent supply, wherein the composition isimpermeable to the passage of analytes that surround and/or encompassthe agent supply. In one embodiment, the agent supply is in a formselected from the group consisting of a depot and/or reservoir. In oneembodiment, the composition comprises a hollow cylindrical tubecomprising at least one passageway on the surface of the composition. Inone embodiment, the agent supply moves out of the reservoir through thehole at zero order. In one embodiment, the composition comprises atleast one end that may be open or plugged using a biocompatible gluewhich may include, but is not limited to, cyanoacrylates, Bioglue epoxyresins, silastics, Teflon®, or polyimide adhesives.

In one embodiment, the present invention contemplates a methodcomprising releasing a therapeutic agent through the ends of the hollowcore (i.e., for example, a cylindrical hollow tube) without any holes onthe housing surface. In another embodiment, one of the ends is pluggedusing a biocompatible glue which may include, but is not limited to,cyanoacrylates, Bioglue®, epoxy resins, silastics, Teflon®, andpolyimide adhesives.

B. The Therapeutic Agent Supply: In one embodiment, the presentinvention contemplates an impermeable therapeutic agent delivery devicecomprising a housing, wherein the housing encompasses a therapeuticagent supply. In one embodiment, the therapeutic agent supply comprisesa solid. In one embodiment, the therapeutic agent supply comprises asemi-solid.

In one embodiment, the present invention contemplates a method offilling an impermeable therapeutic drug delivery device comprising ahousing, wherein the housing is filled with a drug solution. In oneembodiment, the method further comprises evaporating the solution tocreate a solid therapeutic agent supply. In one embodiment, the solidtherapeutic agent supply comprises a powder. In one embodiment, themethod further comprises evaporating the solution to create a semi-solidtherapeutic agent supply. In one embodiment, the semi-solid agent supplycomprises a gel. In one embodiment, the semi-solid agent supplycomprises a hydrogel. In one embodiment, the semi-solid agent supplycomprises a colloid.

The therapeutic agent enclosed in the impermeable matrix may include,but not limited to, ocular agents, anti-neoplastic and/or anti-mitoticagents, steroidal and non-steroidal anti-inflammatory agents, opioidanalgesics and antagonists, anti-cholinergic drugs, adrenergic drugs,anti-adrenergic drugs, local anesthetics, respiratory system drugs,hormones and related drugs, anti-epileptic drugs, anti-parkinsonismdrugs, drugs used in mental illness, cardiovascular drugs, andanti-microbial drugs.

Examples of such ocular agents for treatment of ocular diseases such asdry eye syndrome (DES), uveitis, and age related macular degenerationmay include, but is not limited cyclosporine derivatives;doxycycline-induced protease inhibition; mucin secretion stimulants;adenosine receptor agonists; chloride channel stimulators; anti-TNFagents such as infliximab, adalimumab, and etanercept, anti-interleukintherapy such as daclizumab, and anakinra; interleukin 2 (IL-2) receptorantagonist, vascular endothelial growth factor (VEGF) inhibitors such aspegaptanib, ranibizumab, bevacizumab; and nuclear factor kappa B (NF-kB)inhibitors.

Examples of such antineoplastics and/or antimitotics may include, butnot limited to paclitaxel, docetaxel, doxorubicin hydrochloride,methotrexate, azathioprine, vincristine, vinbiastine, and fluorouracil.

Examples of such steroidal and non-steroidal anti-inflammatory agentsmay include, but not limited to prednisone, dexamethasone,hydrocortisone, estradiol, triamcinolone, mometasone, fluticasone,clobetasol, and non-steroidal anti-inflammatories, such as, for example,acetaminophen, ibuprofen, naproxen, adalimumab and sulindac.

Examples of such opioid analgesic may include, but not limited tomorphine, codeine, thebaine, papaverine, noscapine. Examples of suchopiod antagonist include naloxone and naltrexone.

Examples of such anti-cholinergic drugs may include, but not limited toatropine (e.g., for ophthalmic use as a cycloplegic; mydriatic),scopolamine (e.g., for ophthalmic use as in uveitis, iritis, andiridocyclitis), propantheline bromide (e.g., for treatment of enuresis).

Examples of such adrenergic drugs include, but not limited tonoradrenaline, ephedrine, dopamine, phenylepherine, adrenaline,ephedrine, dobutamine, isoprenaline, adrenaline, isoprenaline,ephedrine, salbutamol, salbutamol, terbutaline, and nylidrine.

Examples of such anti-adrenergic drugs include, but not limited tophentolamine, tolazoline, prazosin, propanolol, timolol, oxprenolol,atenolol, oxprenolol, and alprenolol.

Examples of such local anesthetics include, but not limited tolidocaine, cocaine, tetracaine, benoxinate, benzocaine,butylaminobenzoate, and oxethazine.

Examples of such respiratory systems drugs include, but not limited toanti-tussives such as codeine, morphine, noscapine, oxeladin, andcarbetapentane; antihistamines such as promethazine, diphenhydramine,chlorpheniramine; anti-asthmatic such as adrenaline, ephedrine,salbutamol, terbutaline, theophylline, atropine methonitrate, ketotifen,nedocromil, prednisolone, beclomethasone, and budesonide.

Examples of hormones and related drugs may include but not limited topropylthiouracil, carbimazole, cortisol, prednisolone, paramethasone,betamethasone, ethinyl estradiol, diethylstilbestrol, calcitonin,vitamin D, calcitriol. Examples of anti-epileptic drugs may include butnot limited to phenobarbitone, primidone, phenytoin, mephenytoin,carbamazepine; trimethadione, cloanazepam, diazepam.

Examples of anti-parkinsonism drugs may include but not limited to,levodopa, bromocriptine, lisuride, apomorphine, carbidopa, benserazide,amantadine, deprenyl, trihexyphenidyl, and biperiden. Examples of drugsused in mental illness may include but not limited to, antipsychoticssuch as chlorpromazine, thioridiazine, haloperdol, droperidol,chlorprothixene, thiothixene; antianxiety drugs such as diazepam,lorazepam, alprazolam, propanolol, and anti-depressants such asphenelzine, tranylcypromine, deprenyl, and moclobimide.

Examples of cardiovascular drugs may include but not limited to, cardiacglycosides such as digitoxin, digoxin; anti-arrhythmic drugs such asquinidine, procainamide, propafenone, lidocaine, propanolol, verapamil,diltiazem; anti-anginal and ani-ischaemic drugs such as nitrogylcerine,isosorbide dinitrate; anti-hypertensives such as captopril, enalapril,thiazides, furosemide, spironolactone; anti-restenosis drugs such aspclitaxel, rapamycin, zotarolimus, and tacrolimus.

Examples of anti-microbial drugs may include but not limited to,antibacterial such as penicillins, aminoglycosides, and erythromycin;antifungal such as griseofulvin, ketoconazole; antiviral such asacyclovir, amantadine, antiprotozoal such as chloroquine, metronidazole;anthelmintic such as mebendazole, piperazine, and niclosamide.

Examples of such drugs undergoing clinical trials may include but notlimited to, treatment of conditions such as prostate cancer (e.g.,toremifene citrate, acapodene, flutamide, combination of docetaxel andestramustine, denosumab); brain tumors (e.g., karenitecin, topotecan)and eye diseases (e.g., valganciclovir for treatment of patients withCMV retinitis and AIDS; Celecoxib to treat macular degeneration).

C. The Release Passageways: In one embodiment, the delivery devicecomprises an impermeable matrix which has at least one passageway.Although it is not necessary to understand the mechanism of aninvention, it is believed that the release of an agent is driven bydiffusion and occurs through these passageways. For example, a hollowcylindrical tube is filled with the drug solution, which afterevaporation of solvent changes to solid form. The ends of the tubes aresealed with a bioglue such that the passageways remain the only escaperoute for the drug. When the device comes in contact with the bodilyfluid, the difference in concentrations of the drug inside and outsideof the device causes the drug to diffuse into the bodily fluid havingzero-order kinetics.

In one embodiment, the present invention contemplates a controlledrelease delivery device comprising a therapeutic agent supply, whereinthe agent supply comprises a therapeutically effective amount of atleast one agent effective in obtaining a diagnostic effect or effectivein obtaining a desired physiological or pharmacological effect. In oneembodiment, the delivery device comprises an impermeable housing.

In one embodiment, the present invention contemplates a stablecontrolled release delivery device configured to provide long-termtherapeutic agent delivery. In one embodiment, the diameter thepassageways range from the nanometer scale to the centimeter scale. Inone embodiment, the diameter of the passageways range from approximately5 nanometers-1 centimeter. In one embodiment, the diameter of thepassageways range from approximately 100 nanometers-100 microns. In oneembodiment, the diameter of the passageways range from approximately 1micron-50 microns. In one embodiment, the diameter of the passagewaysrange from approximately 10-30 microns. In one embodiment, the diameterof the passageways range from approximately 15-25 microns. In oneembodiment, the diameter of the passageways are approximately 20microns. The data presented herein show that release kinetics from adrug delivery device of the present invention having dimensions ofapproximately 20 mm long with a 125 micron inside diameter comprising 30micron diameter passageways can be extrapolated to support long termstable controlled agent release for: i) approximately forty-three (43)years using a single passageway embodiment; ii) approximately twenty-two(22) years using double passageway embodiment; or iii) approximatelyfifteen (15) years using a triple passageway embodiment. See, FIG. 7.

A comparison of the release data from Examples II, IV, and VI shows thatby increasing the number of similarly sized holes on a device, the agentrelease rate is a function of number of holes. Hence, an additivepattern in amount of drug released is observed. For example, the amountcrystal violet released from a triple passageway impermeable deliverydevice and a double passageway impermeable device are approximately,three-fold and two-fold the amount released from a single passagewayimpermeable device, respectively, as shown in FIGS. 6-8.

D. The Release Outlet Ports: In another embodiment, the housingcomprises a hollow core (i.e., for example, a cylindrical hollow tube)having at least one outlet port at the end of the core, but does nothave any passageways on the housing surface (e.g., surface passageways).One end of the housing is sealed with a bioglue such that the other endis the only escape route for the therapeutic agent. On contact with abodily fluid, the agent diffuses out having zero-order kinetics. Anybiocompatible adhesive may be used to seal and plug unused outletport(s) at the end of the tubes including, but is not limited to, musselglue, frog glue, cyanoacrylates, Teflon® adhesive, polyimide adhesive,bioglue containing albumin and glutaraldehyde or similar compounds,silastic, epoxy resins and other commonly known glues and adhesives.

In one embodiment, the present invention contemplates a stablecontrolled release delivery device comprising at least one outlet portconfigured to provide long-term therapeutic agent delivery. In oneembodiment, the diameter of the outlet port range from approximately1-100 microns. In one embodiment, the diameter of the outlet port rangefrom approximately 10-75 microns. In one embodiment, the diameter of theoutlet port range from approximately 25-50 microns. In one embodiment,the diameter of the outlet port are approximately 30 microns. The datapresented herein show that release kinetic from a drug delivery deviceof the present invention having dimensions of approximately 20 mm longwith a 125 micro inside diameter comprising a 30 micron outlet port canbe extrapolated to support long term stable controlled agent release forapproximately two (2) years (FIG. 9).

A comparison of the crystal violet release data of Examples IX and IIindicates that as the passageway diameter size increases, the releaserate increases to an amount approximate to the square of ratio of thetwo radii (i.e., for example, {R₁/R₂}²).

E. Medical Device Attachments: In some embodiments, the device can beincorporated (i.e., for example, attached) as part of any other drugdelivery system including, but not limited to, bare metal stents, drugeluting stents, transdermal patches, retinal implants, cochlearimplants, renal implants, grafts and transplants. In other embodiments,the device can be used as part of any medical procedure including, butnot limited to, mechanical thrombectomy for treatment of stroke, drugeluting implants for cancer therapy, drug delivery device to deliverinsulin, gene implant therapy, brain implants to reduce and preventdamage from Alzheimer's, Parkinson's syndrome, or epilepsia, anddelivery of cholinesterase inhibitors, antiretroviral agents, andimmunosuppressants to treat autoimmune disorders such as myastheniagravis, and AIDS. Although it is not necessary to understand themechanism of an invention, it is believed that optimizing therapeuticagent release from a device of the present invention utilize parametersincluding, but not limited to, the route of administration, targeteddiseased condition, or desired release rate provide guidances as to thetype of drug loaded, the amount of drug loaded, dimensions of thedevice, and dimensions and number of holes on the device surface.

In one embodiment, the present invention contemplates an impermeabledrug delivery device attached to a stent. In one embodiment, the stentcomprises a nondegradable polymer. In one embodiment, the non-degradablepolymer stent may be selected from the group comprising Cypher Select®(sirolimus eluting, Cordis Johnson & Johnson) Taxus Liberti® (paclitaxeleluting, Boston Scientific) Endeavor® (zotarolimus eluting, Medtronic)ZoMaxx® (zotarolimus eluting, Abbott) Apollo® (paclitaxel eluting,InTek) Xience® (everolimus eluting, Abbott) or Promus® (everolimuseluting, Boston Scientific). In one embodiment, the stent comprises adegradable polymer. In one embodiment, the degradable polymer stent maybe selected from the group comprising BioMatrix® (biolimus eluting,Biosensors) Infinnium® (paclitaxel eluting, SMT) Nobori® (biolimuseluting, Terumo) Champion® (everolimus eluting, Guidant), and CoStar®(paclitaxel eluting, Johnson & Johnson).

Despite the commercial availability, these drug eluting stents weredesigned and tested before the discovery of LST and its implications.Consequently, most FDA approved stents are still questionable for theirlong term usage. Hence, against the backdrop of these new complications,some embodiments of the present invention comprise therapeutic agentdelivery devices that do not require a polymer to control agent release.Although it is not necessary to understand the mechanism of aninvention, it is believed that such a device should be capable ofdelivering a combination of drugs at concentrations sufficient toinhibit restenosis without delaying the healing of the stent or inducingpost-implantation complications including, but not limited to, LST orrestenosis.

F. Microelectronic Integration: In one embodiment, the present inventioncontemplates an impermeable therapeutic agent delivery device, whereinthe core, housing or other substrates can be integrated withmicroelectronics circuits and microelectromechanical systems (MEMS)structures. In one embodiment, the microelectronic circuit comprises asensor. In one embodiment, the sensor comprises an analyte sensor. Inone embodiment, the sensor comprises a transmitter, wherein thetransmitter signal is received by a remote detector. In one embodiment,the analyte may be selected from the group including, but not limitedto, an inorganic ion, a small organic molecule, a protein, a steroidhormone. In one embodiment, the protein comprises an insulin protein. Inone embodiment, the device comprises an integrated solid circuit capableof monitoring and controlling the release of chemical agents ormedications. In one embodiment, the device comprises an integrated solidcircuit capable of monitoring body analytes and controlling the releaseof chemical agents or medications.

III. Preparation And Loading of a Therapeutic Agent Supply: In oneembodiment, the present invention contemplates a method for loading atherapeutic agent supply comprising a drug delivery device and atherapeutic agent composition. In one embodiment, the compositioncomprises a solid. In one embodiment, the composition comprises asemi-solid. In one embodiment, the solid comprises a polymer matrix. Inone embodiment, the semi-solid comprises a semi-solid. In oneembodiment, the solid comprises a powder. In one embodiment, the loadingmeans may be selected from the group comprising capillary (see, ExampleI), dipping, injecting, using positive or negative pressure, or othercommonly known drug loading methods.

IV. Delivery Device Fabrication: In one embodiment, the presentinvention contemplates a process for fabricating a therapeutic devicecomprising micro-holes on non-planar substrates including, but notlimited to, cylindrical polymer tubes.

In one embodiment, the present invention contemplates a process forfabrication of micro-holes on non-planar surfaces. In one embodiment, amicro-hole can be formed on a wide range of non-planar substrates, metalor non-metal, and with varying shapes, including cylindrical tubes.Depending on the application, a micro-hole can vary in size including,but not limited to, a fraction of a micron to hundreds of microns indiameter. In one embodiment, the present invention contemplates afabrication process comprising photo-lithography and reactive ionetching. In another embodiment, the present invention contemplates afabrication process using a mold. Devices containing micro-holesfabricated by the present invention can be used for a wide range ofapplications including, but not limited to, medical, bio-material,including implantable medical devices and controlled drug deliverysystems. In one embodiment, the method is capable of fabricatingmicro-hole structures comprising complex geometries on non-planarsubstrates such as the micro electromechanical systems (MEMS) andmicroelectronics devices for a wide range of applications.

A. Background: The technology to fabricate micro-structures on planarsilicon wafers is well developed and has led to the use of planarintegrated circuits in everyday electrical and electronic devices.Planar technology can be extended to fabricate MEMS and nanotechnologydevices for a wide range of applications in medicine and bio-materials.Nonetheless, planar microfabrication technology has many disadvantageswhen attempting to fabricate devices on non-planar substrates including,but not limited to, a cylindrical polymer tube.

For example, one common current method to fabricate micro-holes on acylindrical tube is by laser ablation. Laser ablation is a serialprocess which is time consuming and difficult to be used for massproduction. The laser ablation method has a number of limitations: i)the diameter of the micro-hole is normally larger than 15 microns; ii)it is difficult to control micro-hole shape; iii) it is difficult tocontrol micro-hole depth; and iv) laser beam usually damages thematerial around the micro-hole.

Micro-structures or micro-devices on non-planar substrates canpotentially be used for a wide range of applications for thepharmaceutical industry. The present invention describes a process ofmicro-fabrication to create micro-structures and micro-devices onnon-planar substrates. The micro-structure fabricated by the disclosedmethod can be integrated into a support structure to form complexdevices for a wide range of applications. In some embodiments, thepresent invention contemplates a process for fabricatingmicro-structures, and/or microdevices comprising micro-holes, whereinthe microdevices comprise non-planar surfaces, comprising: 1)fabricating at least one trench on a planar substrate, such as a siliconwafer, to hold a micro-structure with a non-planar substrate such as apolymer tube; 2) fabricating a micro-hole on non-planar substrates usinga combination of lithography, e.g., photolithography, reactive ionetching and/or chemical etching; 3) a non-planar substrate comprisingeither a metal or a non-metal having varying shapes capable of beingplaced into a planar support structure including, but not limited to, asilicon wafer trench: 4) micro-holes varying in size from a fraction ofa micron to hundreds of microns, and 5) micro-holes varying in shapeincluding, but not limited to, circular, rectangular, triangular,elliptical and square.

B. Delivery Device Fabrication Methods: The technologies to fabricatemicro-structures on planar silicon wafers have been previously reported.But it is difficult to fabricate on non-planar substrate, including, butnot limited to, a cylindrical polymer tube. Current methods to fabricatemicro-holes on a cylindrical tube are usually performed by laserablation. Laser ablation is a serial process which is time consuming anddifficult to adopt for mass production. The micro-holes fabricated bylaser ablation normally have diameters larger than 15 microns and it isdifficult to control the shape and depth of the micro-hole. In addition,laser beam usually burns and damages the material around themicro-holes, which is not desirable for many medical applications.

The present invention contemplates a process for fabrication ofpassageways on non-planar surfaces. The passageway can be formed on awide range of substrates, metal or non-metal, and shapes, such as tubes,depending on the application. The passageway varies in size from afraction of a micron to hundreds of microns in diameter and can have avariety of shapes. In one embodiment, the fabrication process is basedon lithography and reactive ion etching technologies. In anotherembodiment, the process first fabricate a mold consisting of a substratewith trenches and through holes located in trenches, then a non-planarsubstrate is placed in the mold to form micro-hole structures byetching. Such devices containing the passageways of the presentinvention can be used for a wide range of medical and bio-materialsapplications, including the use for medical implantation and controlleddrug delivery.

The modified lithographic technique described herein has many advantagesover current techniques. For example, i) the process is a parallelprocess and suitable for mass production; ii) the process is associatedwith a lower cost; iii) the process greatly improves the capabilitiesand control in producing holes of non-circular shapes and varying sizeson non-planar surfaces; iv) the process can be integrated with MEMS andsolid circuit sensors to form devices for a range of applications,including microelectronics, medical delivery and bio-materials.

The present invention discloses a process for fabrication of passagewayson non-planar surfaces. Depending on the application, the passagewayscan be formed on a wide range of substrates, metal or non-metal, andwith varying shapes including a tubular form. In some embodiments,passageway varies in size from a fraction of a micron (i.e., forexample, approximately, 0.01 micron) to hundreds of microns (i.e., forexample, 900 microns) in diameter.

Some embodiments of the present invention provide advantages overconventionally used microelectronic photolithographic processingtechnologies. For example, conventional photolithographic techniques arelimited to planar surfaces, while the present invention has describedphotolithographic fabrication of non-planar surfaces (i.e., for example,metal or non-metal). In one embodiment, the fabrication comprises theetching of passageways (i.e., for example, micro-holes) on a non-planarsurface. In one embodiment, a special structural element (i.e., forexample, a trench pattern) is fabricated first on a silicon wafer tohold the non-planar surface material. The planar substrate can be anymaterial other than a silicon wafer, depending on the structure and theapplication of interest. Accordingly, the process steps will have to beadjusted. Other trench structures with other shapes can be fabricated ifdesired, depending on the shape of the non-planar substrates.

This method provides significant advantages over current technology thatfabricates micro-holes on a non-planar surfaces requiring laser ablationwhich is a time consuming serial process and expensive. On the otherhand, the present invention discloses a process that can be performed inparallel and therefore is well-suited for mass production. Thisinvention also provides another advantage by enabling the fabrication ofa variety of passageways on many non-planar surfaces simultaneously,thus significantly reducing the manufacturing cost. In addition, thelithographic technique makes it possible to form individual passagewaysor a group of passageways having different sizes and shapes including,but not limited to, circular, elliptical, square and rectangular shapes.

FIG. 1 shows a top view of several embodiments of the invention. In eachembodiment, a therapeutic agent delivery device 1 comprising a hollowcylindrical tube 2 is depicted which may be used as a reservoir fortherapeutic agents (i.e., for example, a drug). The surface of thedevice comprises a plurality of passageways 3, wherein the holes on thedevice are equidistant from each other and from the end of the tube.Upper drawing: A device comprising a single passageway. Middle drawing:A device comprising two passageways. Lower drawing: A device comprisingthree passageways.

FIG. 2 shows a cross-sectional view of one embodiment of the therapeuticagent delivery device during administration of the agent. The device 1comprises a hollow cylindrical tube 2 and is filled with a diagnostic,therapeutic, or prophylactic agent 4 while being placed against ananatomical site 5. The device is positioned to release the agent isdirectly to the targeted anatomical site in an unidirectional mannerthrough the passageways 3 (see arrows). FIG. 3 shows one embodiment of acarrier 6 to which a therapeutic agent delivery device may be attached.FIG. 4 shows one embodiment depicting five (5) therapeutic agentdelivery devices 1, comprising three passageways 3 each, attached to astent 7. FIG. 5 shows one embodiment depicting three (3) therapeuticagent delivery devices 1, comprising three (3) passageways 3 each,attached to an adhesive patch 8.

FIG. 6 shows exemplary data of zero order release kinetics of crystalviolet (e.g., a dye, and anti-fungal agent) for twenty-eight (28) daysfrom three embodiments of the therapeutic drug delivery device. Circles:A device with one surface passageway (R²=0.9945). Squares: A device withtwo surface passageways (R²=0.9998). Triangles: A device with threesurface passageways (R²=0.9998). FIG. 7 shows exemplary data of thepercentage of crystal violet (dye, antifungal-agent) released atzero-order for twenty-eight (28) days from three different embodimentsof the therapeutic drug delivery device. Circles: A device with onesurface passageway (R²=0.9945). Squares: A device with two surfacepassageways (R²=0.9999). Triangles: A device with three surfacepassageways (R²=0.9998). FIG. 8 shows exemplary data demonstrating thelinearity of cumulative agent release between the three embodimentstested in FIGS. 6 and 7 after twenty-eight (28) days (R²=0.9962).Circle: A device with one surface passageway. Square: A device with twosurface passageways. Triangles: A device with three surface passageways.FIG. 9 shows exemplary data of zero order release kinetics of crystalviolet for five (5) days from one embodiment of the therapeutic agentdelivery device, wherein there are no holes on the device surface, buthas a single outlet port on one end of the device (R²=0.9993).

In one embodiment, the process of forming micro-holes requires first thefabrication of a mold consisting of a planar substrate with trenches andthrough holes located in trenches as illustrated in FIG. 10. Thetrenches can hold the miniature substrates, such as polymer tubes. Thenthe whole assembly can be flipped over and then etched from the backsideto produce through holes in the targets such as the wall of abiodegradable tube. In this way, the planar substrate works as a mold.The mold can be made from a variety of materials, including a siliconwafer, a glass substrate, and a metal plate. The etching technique canbe chosen from a number of techniques including but not limited tophysical etching, chemical etching, reactive ion etching, laserablation, and cutting by plasma torches.

FIG. 10 shows a schematic drawing of a mold 1000 with trenches 1002 andthrough holes 1004. Although the through holes 1004 shown in the figureare circular, they can be formed in other shapes as desired.

In one embodiment, the mold can be fabricated on a silicon wafer usingmicro-fabrication technology. An example of the process flow is shown inFIG. 11A-11D where all figures are shown in a cross-sectional view. Tostart, the silicon mold can be fabricated on a double side polishedwafer 1101. The fabrication process begins with a deposition of maskinglayers 1103 and 1105 on the topside and the backside of the waferrespectively, as shown in FIG. 11A. Low stress silicon nitride formed bylow pressure chemical vapor deposition (LPCVD) is a preferred materialfor masking layer 202 and 203. In FIG. 11B, a photolithography step isapplied to define an opening on the topside which is further transferredthrough the silicon nitride layer by reactive ion etching (ME).Alignment marks are fabricated in this step but not shown in the figure.Then a wet anisotropic etching using TMAH is applied to etch a trench1107 in the silicon wafer with a silicon nitride layer as an etchingmask. The trench sidewalls 1109 are smooth planes which work as etchstop layers. The V-groove trench 1107 will be used to hold the tubes.After that, the second photolithography step is applied to the backsideof wafer to define a window pattern which is aligned to the trench onthe topside with the help of alignment marks. RIE and wet anisotropicetching are used again to transfer the window 1111 pattern into thesilicon wafer and expose the smooth planes 1113 as shown in FIG. 11C. InFIG. 11D, the third lithography step is applied to define the holestructure which is then etched into a through hole 1115 by ME. Anoptional step to harden the mold surface is to apply a silicon nitridelayer on the surface, which is not shown in the figure.

In one embodiment, the method comprises preparing a trench structure ona planar substrate, such as a silicon wafer 10 (FIG. 12A). In oneembodiment, a trench structure on the silicon wafer was fabricated by acombination of photolithography and anisotropic etching wherein asilicon dioxide layer 20 was deposited on a silicon wafer 10, followedby the deposition of a chromium layer 30 by physical vapor deposition(FIG. 12B). The silicon dioxide 20 and chromium 30 layers serve asetching mask layers for the subsequent process steps. The silicon wafercan be either a (110, FIG. 12E) or a (100, FIG. 12F) wafer, depending onthe choice of “U” shaped or “V” shaped trenches to be fabricated by wetanisotropic etching. After spin-coating of a photo-resist 40 layer, atrench structure 50 was created by photolithography on the photo-resistlayer 40 as shown in FIG. 12C. The trench direction is aligned to thewafer flat. Alignment marks 140 were also created in this step. See,FIG. 11A. The alignment marks were designed to position future patterns,e.g., micro-holes, to the desired places of non-planar substrates, suchas polymer tubes, which would placed into trenches on the silicon wafer.The trench structure was then transferred through the chromium layer tothe silicon oxide layer by reactive ion etching (FIG. 12D). This wasfollowed by a second reactive ion etching step transferring the trenchstructure through the oxide layer to the silicon substrate using thechromium layer as the etching mask. This step produced the trenchstructures 60. The final step to fabricate the trench structure was awet anisotropic etching step, which was used to remove the un-wantedsilicon materials. The processing sequence as described produced a “U”shaped trench 70 in a (110) wafer, or a “V” shaped trench 80 in a (100)wafer as shown in FIGS. 12E and 12F, respectively. The depth and widthof the trench structures can be controlled by the geometry of thephoto-mask and the anisotropic etching time. The depth and width oftrenches should be slightly larger than the dimension of the non-planarsubstrate. The structures with the U shape or the V shape trench canalso be used as to form a mold. An example of a V shape trench is shownin FIG. 11B.

FIGS. 13A-13C shows the plan view of the schematic silicon moldfabricated following the process shown in FIGS. 11A-11D. FIG. 13A is thetopside 1300 of the wafer with wafer flat 1302. As shown, the designlooks similar to that in FIG. 10 with trenches 1304 and through holes1306. Two alignment marks 1308 and 1310 are fabricated in this step asshown in FIG. 11A. FIG. 13B shows the backside 1312 of the wafer. Windowstructures 1314 and through holes 1306 are aligned with the trenches1304 on the topside. The window structures 1314 correspond to 1111 inFIG. 11C. FIG. 13C shows an enlarged view of a single window structure1312 in FIG. 13B. Four planes 1316 here correspond to 1113 in FIG. 11Cand the through holes 1306 in FIGS. 13A-13C correspond to the hole 1115in FIG. 11D.

FIG. 13D shows a scanning electron microscopy image of a “U” shapedtrench fabricated on a silicon wafer. The width and depth of the trenchis about 100 microns and 80 microns, respectively.

After the mold is fabricated, the fabrication of micro-holes in thetubes is rather simple. As shown in FIG. 14A, first the tubes 1402 areinserted into the trenches on the topside of the mold. Adhesives may ormay not be applied to part of the trenches to hold the tubes in thetrenches. Another substrate 1404 may also be used to push tubes towardthe bottom of the trenches. Then the whole assembly is flipped over sothat the backside of the mold is facing up as shown in FIG. 14B. Anetching step is performed to transfer the through hole patterns of themold to the tubes and finally holes 1408 on tubes are obtained. In oneembodiment, reactive ion etching is used as indicated by the reactiveplasma 1406.

The planar substrate can be any material other than a silicon wafer,depending on the structure and the application of interest. Accordingly,the process steps will have to be adjusted. Other trench structures withother shapes can be fabricated if desired, depending on the shape of thenon-planar substrates.

In one embodiment, the fabrication of passageways, such as micro-holes,on a non-planar substrate starts with inserting the non-planar substrateinto the trench structure of the supporting substrates. In oneembodiment, an adhesive is applied in the trench to hold the non-planarsubstrate in place. In one embodiment, the adhesive is a photo-resist.The assembly of the supporting substrate with the non-planar substrateis then handled as a conventional subject with a planar substrate forsubsequent process steps.

In one embodiment, the non-planar substrate is a polymer tube 90 shownin FIGS. 15A-15E. In one embodiment, it was inserted into a “U” shapedtrench as shown in FIG. 15A. In one embodiment, a masking layer 100 wasdeposited on the wafer as well as the surface of the polymer tube 90, asshown in FIG. 15B. In one embodiment, the masking layer 100 is achromium layer. The alignment marks were protected during the chromiumdeposition. This was followed with spin-coating of a photo-resist layer110 on top of the polymer tube as shown in FIG. 15C. After carefulalignment, micro-holes 120 were fabricated following a sequence ofsteps: first, defining the micro-holes using photolithography with aphoto-resist layer 110. Then the micro-hole structures were transferredthrough the chromium layer 100 by reactive ion etching. Finally, asecond reactive ion etching step was applied to transfer the micro-holestructure through the tube wall to yield fully penetrated micro-holes130 on the tube. FIG. 13D shows an optical microscopy image of apolyimide tube with a hole of about 20 microns in diameter fabricated bythis method.

FIG. 16 illustrates a schematic of one embodiment of a carriercomprising a skeleton of a bare metal stent. FIG. 17 shows one anotherembodiment of a therapeutic agent delivery device with differentdiameters that is 200 microns, 400 microns, and 600 microns. The devicecomprises of one outlet port 32 without any passageways on the surfaceof the device. One end of the device 31 is sealed with a heat shrinktube or a biocompatible adhesive. Upper drawing: A device with insidediameter of 200 microns. Middle drawing: A device with inside diameterof 400 microns. Middle drawing: A device with inside diameter of 600microns.

FIG. 18 presents an exemplary photomicrograph showing release of crystalviolet 71 from a device 72 comprising two passageways 73 into aphosphate buffered saline solution 74. Release of drug from each hole isindependent of the other. The dimension of the tube is 1000 microns andthe holes size is approximately 400 microns. These bigger sized tubesand holes were selected to visually observe the release mechanism, andare not intended to limit the present invention. FIG. 19 shows exemplarydata of zero order release kinetics of crystal violet (e.g., a dye, andanti-fungal agent) for twenty-eight (28) days from three embodiments ofthe therapeutic drug delivery device. Circles: A device with one outletport and inside diameter of 200 microns (R²=0.9667). Squares: A devicewith one outlet port and inside diameter of 400 microns. Triangles: Adevice with one outlet port and inside diameter of 600 microns(R²=0.9355). FIG. 20 shows exemplary data comparing cumulative amount ofcrystal violet released from the three groups (200 microns, 400 microns,and 600 microns) for seven days. The release rates follow a quadraticrelationship as is evident by the equations of line for each day, whichare in the form: y=a·x²+bx+c, and their corresponding R² values whichare close to 1.000. Hence, the rate of release of drug is alsoproportional to the square of the radius, that is,

$\frac{dM}{dT}\alpha \; {r^{2}.}$

V. Therapeutic Applications: In one embodiment, the present inventioncontemplates methods for treating medical conditions and diseases. Forexample, such conditions may include, but are not limited to,cardiovascular disease, cancer, diabetes, pain, Parkinson's disease,epilepsy, or ocular diseases.

A. Cardiovascular Diseases: In one embodiment, the present inventioncontemplates a method for treating a cardiovascular disease. In oneembodiment, the cardiovascular disease may include, but not limited to,stenosis, restenosis, stroke, myocardial infarction, congestive heartdisease, high blood pressure, angina, atherosclerosis, or thrombosis. Inmany cases, cardiovascular diseases are treated with drug eluting stents(DES). While easily inserted into specific cardiovascular vessels theseDESs have encountered significant biocompatibility problems.

1. Clinical Problems Associated with Drug Eluting Stents: Since theirinception, DESs have significantly reduced the rate of clinicalrestenosis as compared to bare metal stents (BMS) and conventionalballoon angioplasty. Moses et al., “Sirolimus-Eluting Stents VersusStandard Stents in Patients with Stenosis in a Native Coronary Artery” NEngl Med 349:1315-1323 (2003); and Park et al., “A Paclitaxel-ElutingStent for the Prevention of Coronary Restenosis” N Engl Med348:1537-1545 (2003). An ideal drug eluting stent has been suggested topossess characteristics including, but not limited to: i) polymersallowing ideal drug release; ii) drugs should inhibit vascular smoothcell proliferation and inflammation and prevent restenosis; iii) thestent becomes part of the vasculature to prevent any lateinflammations/thrombosis; iv) the stent allows collateral blood vesselcirculation. Baffour et al., “Enhanced Angiogenesis and Growth ofCollaterals by In Vivo Administration of Recombinant Basic FibroblastGrowth Factor in Rabbit Model of Acute Lower Limb Ischemia:Dose-Response Effect of Basin Fibroblast Growth Factor” Vasc Surg16:181-191 (1992); and Geerts A M, “Colic I. Angiogenesis in PortalHypertension: Involvement in Increased Splenehnic Blood Flow andCollaterals?” Acta Clin Belg 62:271-275 (2007). However, even beforeintroduction of the first commercial DES, potential problems wereidentified that may arise due to “nonerodable thick polymer sleeve, veryhigh concentration of the active drug, extended release kinetics, loosestent architecture, and inhomogeneous drug delivery”. Virmani et al.,“Mechanism of Late In-Stent Restenosis After Implantation of PaclitaxelDerivate-Eluting Polymer Stent System in Humans” Circulation106:2649-2651 (2002).

Studies have shown an increase in the rate of death and myocardialinfarction in patients following 18 months to 3 years after stentingwith CYPHER®, and TAXUS®. Aziz et al., “Late Stent Thrombosis Associatedwith Corona Aneurysm Formation After Sirolimus-Eluting StentImplantation” Invasive Cardiol 19:E96-8 (2007); Camenzind E., “Treatmentof In-Stent Restenosis—Back to the Future?” N Engl Med 355:2149-2151(2006); Camenzind et al., “Stent Thrombosis Late After Implantation ofFirst-Generation Drug-Eluting Stents: A Cause for Concern” Circulation15:1440-1455 (2007); and Pfisterer M. E., “The BASKET-LATE-Study. BaselStent Cost-Effectiveness Trial—Late Thrombotic Events Trial” Herz 31:259(2006). A statement issued by United States Food and Drug Administrationalso identified adverse cardiac events in patients treated with drugduring stents. fda.gov/cdrlVnewslOgl406 (2007).

The reported problems are usually associated with late stent thrombosis(LST) which blocks the arteries increases the risk of myocardialinfarction. Interestingly, it has been reported that bare metal stents(BMS) have lower MACE rates as compared to DES. Kim et al.,“Stent-Related Cardiac Events After Non-Cardiac Surgery: Drug-ElutingStent Bare Metal Stent” lnt J Cardiol 123:353-354 (2008); Lagerqvist etal., “Long-Term Outcomes with Drug-Eluting Stents Versus Bare-MetalStents in Sweden” N Engl Med 356:1009-1019 (2007); and Steinberg et al.,“Drug-Eluting Stent Thrombosis Bare Metal Stent Restenosis: Finding theLesser of Two Evils” Am Heart Hosp 5:151-154 (2007). However, the exactnature of drug-eluting stent thrombosis is still unclear, for example,what causes it, how often it occurs, under what circumstances it occurs,or what the risk of occurrence is in a given patient.

2. Late Stent Thrombosis (LST): Polymer coatings have been named as onefactor associated with the failure of DES. Under mechanical stress suchas during implantation of stents, polymer coatings might crack leadingto injury to arterial wall. Injury activates platelet aggregation andblood clotting leading to LST. Generally, it takes 28 days for the baremetal stent to become part of the vasculature (endothelialization).Cracking of polymers may also lead to drug dumping at the injuredarterial site delaying the healing of the stent. The incompleteendothelialized stent becomes an attractive site for platelet adhesionincreasing the probability of LST. The drug overexposure also preventscollateral blood vessel formation, thereby increasing the stress on theheart.

Alternatively, polymer hypersensitivity might incite inflammationreactions. The occurrence of such allergic reactions has supportiveevidence such as a marked activation of inflammatory cells (i.e., forexample, leucocytes) at the site of a stent. Li et al., “Is InflammationContributor for Coronary Stent Restenosis?” Med Hypotheses 68:945-951(2007). Leukocytes have also been linked to the formation of neointimalhyperplasia along with platelet adhesion indicating the central role ofinflammation in both restenosis and LST. Golino et al., “Inhibition ofLeukocyte and Platelet Adhesion Reduces Neointimal Hyperplasia AfterArterial Injury” Thromb Haemost 77:783-788 (1997); Sainani et al., “TheEndothelial Leukocyte Adhesion Molecule. Role in Coronary ArteryDisease” Aeta Cardiol 60:501-507 (2005; Wang et al., “Enhanced LeukocyteAdhesion to Interleukin-I Beta Stimulated Vascular Smooth Muscle Cellsis Mainly Through Intercellular Adhesion Molecule-l” Cardiovasc Res28:1808-1814 (1994).

3. Restenosis: Restenosis is believed to result from mechanismsincluding, but not limited to, inflammation or cell proliferation at thesite of injury in the stented artery. Drugs such as paclitaxel andsirolimus are being currently used in drug eluting stents to preventscar tissue growth and neointima formation. In general, these drugs werechosen for potency, and general effects on suppressing cellular growthwithout targeting the underlying vascular disease.

Restenosis is believed to result from injury to an arterial wall duringstent implantation and occurs within 6-12 months of the procedure. Incontrast, LST mainly occurs when the stent is not able to endothelializeand usually occurs after 12 months of stenting. Classic restenosisoccurring with bare metal stents (i.e., for example, non-drug coated)comprises progressive, instead of rapid, symptoms and affects 25-30% ofthe treated patients. In contrast, LST is believed to result of suddenformation of a blood clot within the stent. Though LST is observed inonly 1.5-5% of the patients but morbidity and mortality rates are quitehigh, making it more dangerous. Holmes D R, Jr., “Incidence of LateStent Thrombosis with Bare-Metal, Sirolimus, and Paclitaxel Stents” RevCardiovasc Med 8(Suppl 1): S11-18 (2007).

A. Anti-Restenosis Drugs: Zotarolimus (formerly known as ABT-578) is asirolimus analogue having cytostatic properties. Buellesfeld et al.,ABT-578-eluting stents. “The Promising Successor of Sirolimus- andPaclitaxel-Eluting Stent Concepts?” Herz 29167-29170 (2004). Zotarolimusmay be synthesized by substituting the native hydroxyl group with thetetrazole ring at position 40 in rapamycin. It is believed extremelylipophilic and a very low water solubility, hence very little isreleased to the circulation. Seabra-Gomes R., “Percutaneous CoronaryInterventions with Drug Eluting Stents for Diabetic Patients” Heart2006; 92:410-419 (2006). Everolimus is synthesized from sirolimus bysubstituting a —CH₂OH group at position 40. Like sirolimus, everolimusalso inhibits mammalian target of rapamycin (mTOR). Experimental studieshave shown that oral everolimus also inhibits smooth muscle cellproliferation and prevents neointimal thickening and arteriosclerosis.Farb et al., “Oral Everolimus Inhibits In-Stent Neointimal Growth”Circulation 106:2379-2384 (2002); Waksman et al., “Optimal Dosing andDuration of Oral Everolimus to Inhibit In-Stent Neointimal Growth inRabbit Iliac Arteries” Cardio-vasc Revasc Med 7:179-184 (2006).Everolimus has been reported to have a better pharmacokinetic profileand bioavailability compared with sirolimus. Patel et al., “Everolimus:Immunosuppressive Agent in Transplantation” Expert Opin Pharmacother7:1347-1355 (2006). Everolimus has also been reported to absorb intotissues more rapidly than sirolimus and may have a longer cellularresidence time and activity. Grube et al., “Everolimus for Stent-BasedIntracoronary Applications” Rev Cardiovasc Med 5(Suppl 2):S3-S8 (2004).

Biolimus A9 (Biosensors International, Singapore) is reported as ahighly lipophilic sirolimus analog. Biolimus has been reported as welltolerated and effective having similar immunosuppressive potency assirolimus. However, it appears that Biolimus A9 is more rapidly absorbedthan sirolimus by the vessel wall and enters smooth muscle cellmembranes more readily, thereby causing cell cycle arrest at G₀. Costaet al., “Angiographic Results of the First Human Experience with theBiolimus A9 Drug-Eluting Stent for De Coronary Lesions” Am Cardiol98:443-446 (2006). Recently release data indicates that Biolimus A9showed significantly less neointimal formation as compared withpaclitaxel. Chevalier B., “NOBORI 1: Part A Prospective, RandomizedTrial of Biolimus A9 and Paclitaxel-Eluting Stents: 9-Month Clinical andAngiographic Follow-Up” Transcatheter Cardiovascular TherapeuticsSymposium (2006).

Tacrolimus (also FK-506, Fujimycin, Prograf) is a hydrophobic macrolideimmunosuppressant produced by Streptomyces tsukubaensis. Goto et al.,“Discovery of FK-506, Novel Immunosuppressant Isolated from StreptomycesTsukubaensis” Transplant Proc 19:4-8 (1987). Tacrolimus is widely usedto prevent allograft rejection after organ transplantation. Although itis not necessary to understand the mechanism of an invention, it isbelieved that tacrolimus is a noncytotoxic T cell inhibitor, whichcauses cell apoptosis following growth arrest in the G₀ phase of thecell cycle. Gottschalk et al., “Apoptosis in B Lymphocytes: the WEHI-231Perspective” Immunol Cell Biol 73:8-16 (1995). A protein-engineerednanoparticle albumin bound paclitaxel (nab-paclitaxel) is commerciallyavailable and may be useful for the treatment of coronary and peripheralartery restenosis (Coroxane®, Abraxis Bioscience, Inc.). Coroxane®, likeits oncology counterpart Abraxane®, is a protein stabilized emulsionthat is believed to enhance the solubility of water insolublepaclitaxel. The albumin formulation may also reduce toxicitiesassociated with a solubility enhancing excipient, Cremophor EL®. Greenet al., “Abraxane, Novel Cremophor-Free, Albumin-Bound Particle Form ofPaclitaxel for the Treatment of Advanced Non-Small Cell Lung Cancer” AnnOncol 17:1263-1268 (2006). As a result, the solubility of paclitaxel isimproved and the non-drug related toxicities are eliminated. A Phase IIclinical study tested twenty three (23) patients randomized to one offour doses (10, 30, 70, or 100 mg/m²), wherein doses betweenapproximately 10-30 mg/m² were found to be safe and effective. Margoliset al., “Systemic Nanoparticle Paclitaxel (Nab-Paclitaxel) for In-StentRestenosis (SNAPIST-I): First-In-Human Safety and Dose Finding Study”Clin Cardiol 30:165-170 (2007).

Docetaxel is commercially available (Taxoter®, Sanofi-Aventis) andapproved as an anti-mitotic drug used for the treatment of breast,ovarian and non-small cell lung cancer. Clarke et al., “ClinicalPharmacokinetics of Docetaxel” Clin Pharmacokinet 36:99-114 (1999).Docetaxel is a semi-synthetic analogue of paclitaxel and differs frompaclitaxel at two positions in its chemical structure. For example,docetaxel has a hydroxyl functional group on carbon 10, whereaspaclitaxel has an acetate ester and a tert-butyl substitution exists onthe phenylpropionate side chain. The carbon 10 functional group changecauses docetaxel to be more lipid soluble than paclitaxel. Docetaxel isbelieved to be a microtubule polymerizing agent, and may have improvedantiproliferative properties as compared to paclitaxel. Yasuda et al.,“Local Delivery of Low-Dose Docetaxel, Novel Microtubule PolymerizingAgent, Reduces Neointimal Hyperplasia in Balloon Injured Rabbit IliacArtery Model” Cardiovasc Res 53:481-486 (2002). Docetaxel, however, hasbeen associated with cytotoxicity, which has been reported to occur in adose-dependant manner. Silvestrini et al., “In Vitro Cytotoxic Activityof Taxol and Taxotere on Primary Cultures and Established Cell Lines ofHuman Ovarian Cancer” Stem Cells 11:528-535 (1993). Docetaxel has thepotential as a therapeutic for preventing restenosis, but moreimprovement is needed for better safety and efficacy.

Curcumin (diferuloylrnethane) is believed to be a polyphenolic yellowpigment found in the Indian spice, tumeric (a powdered rhizome ofCurcurna longa Linn). Huang et al., “Inhibitory Effects of DietaryCurcumin for Stomach, Duodenal, and Colon Carcinogenesis in Mice” CancerRes 54:5841-5847 (1994). Curcumin is believed to exhibit variousbiological activities including, but not limited to, anti-proliferativeactivity, anti-inflammatory, antioxidant activity, wound healingability, and anti-microbial activity. Dorai et al., “Role ofChemopreventive Agents in Cancer Therapy” Cancer Lett 215:129-140(2004); Gupta et al., “Dietary Antioxidant Curcumin Inhibits MicrotubuleAssembly Through Tubulin Binding.” FEBS J 273:5320-5332 (2006); and Rubyet al., “Antitumour and Antioxidant Activity of Natural Curcuminoids”Cancer Lett 94:79-83 (1995).

Although it is not necessary to understand the mechanism of aninvention, it is believed that at least two mechanisms contribute torestenosis including, but not limited to, proliferation of vascularsmooth muscle cells and inflammation at the site of injury. It isfurther believed that inflammation reactions may be initiated by abuild-up of reactive oxygen species (i.e., for example, ROS, or freeradicals) at an arterial site. Like paclitaxel, curcumin inhibits cellproliferation by stabilizing microtubule assembly through tubulinbinding. In addition, curcumin may reduce nitric oxide (NO) levelsthereby acting as a suitable antioxidant. Ukil et al., “Dos Curcumin,the Major Component of Food Flavour Turmeric, Reduces Mucosal Injury inTrinitrobenzene Sulphonic Acid-Induced Colitis” Br Pharmacol 139(2):209-218 (2003). The natural healing powers of curcumin make it anexcellent candidate for treatment and prevention of restenosis.

Resveratrol (trans-3, 4, 5-trihydroxystilbene). is believed to be aphytoalexin found in grapes and other medicinal plants that protectsthem against fungal infections. Docherty et al., “ResveratrolSelectively Inhibits Neisseria Gonorrhoea and Neisseria Meningitidis”Antimicrob Chemother 47:243-244 (2001). Resveratrol has been suggestedas a possible answer for the observed ‘French paradox’. The ‘Frenchparadox’ refers to the observation that a high consumption of red wineis associated with relatively low incidences of coronary heart diseases.Kopp P., “Resveratrol, Phytoestrogen Found in Red Wine: A PossibleExplanation for the Conundrum of the ‘French Paradox’?” Eur Endocrinol138:619-620 (1998). Additionally, resveratrol is also a widely reportedanti-fungal, anti-bacterial, anti-viral, anti-oxidant, and ananti-inflammatory agent. de la Lastra et al., “Resveratrol asAntioxidant and Prooxidant Agent: Mechanisms and Clinical Implications”Biochem Soc Trans 35:1156-1160 (2007); Docherty et al., “ResveratrolInhibition of Herpes Simplex Vires Replication” Antiviral Res 43:145-155(1999): Elmali et al., “Effects of Resveratrol in InflammatoryArthritis” Inflammation 30:1-6 (2007); Kasdallah-Grissa et al.,“Resveratrol, a Red Wine Polyphenol, Attenuates Ethanol-InducedOxidative Stress in Rat Liver” Life Sci 80:1033-1039 (2007); and Rahmanet al., “Regulation of Inflammation and Redox Signaling by DietaryPolyphenols” Biochem Pharmacol 72:1439-1452 (2006). Resveratrol is alsobelieved to block human platelet aggregation and vascular smooth musclecell proliferation inhibiting thrombosis and inducing apoptosis whichsuggests its potential use against restenosis. Mnjoyan et al., “ProfoundNegative Regulatory Effects by Resveratrol Vascular Smooth Muscle Cells:Role of p53-p21 (WAF1/CIP I) pathway” Biochem Biophys Res Commun311:546-552 (2003); Olas et al., “Resveratrol, a Phenolic Antioxidantwith Effects on Blood Platelet Functions” Platalets 16:251-260 (2005);Pace-Asciak et al., “The Red Wine Phenolics Trans-Resveratrol andQuercetin Block Platelet Aggregation and Eicosanoid Synthesis:Implications for Protection Against Coronary Heart Disease” Clin ChimActa 235:207-219 (1995). Poussier et al., “Resveratrol Inhibits VascularSmooth Muscle Cell Proliferation and Induces Apoptosis” Vasc Surg42:1190-1197 (2005).

B. Diabetes: In one embodiment, the present invention contemplates amethod for treating diabetes using an impermeable therapeutic agentdelivery device. In one embodiment, the delivery device providescontrolled release of the agent. In one embodiment, the agent comprisesinsulin. In one embodiment, the device further comprises a glucosesensor. In one embodiment, the glucose sensor readout is transmitted toa remote detector. In one embodiment, the device is implanted within acardiovascular vessel. One advantage of this method is that a diabeticpatient receiving treatment using a delivery device comprising a glucosesensor would not be required to perform routine tests for blood sugarlevels.

Diabetes is a chronic (lifelong) disease marked by high levels of sugarin the blood. Insulin is a hormone produced by the pancreas to controlblood sugar. Diabetes can be caused by too little insulin, resistance toinsulin, or both. People with diabetes have high blood sugar. because:i) their pancreas does not make enough insulin and/or ii) their muscle,fat, and liver cells do not respond to insulin normally.

Type 1 diabetes is usually diagnosed in childhood. Many patients arediagnosed when they are older than age 20. In this disease, the bodymakes little or no insulin. Daily injections of insulin are needed. Theexact cause is unknown. Genetics, viruses, and autoimmune problems mayplay a role. Type 2 diabetes is far more common than type 1. It makes upmost of diabetes cases. It usually occurs in adulthood, but young peopleare increasingly being diagnosed with this disease. The pancreas doesnot make enough insulin to keep blood glucose levels normal, oftenbecause the body does not respond well to insulin. Many people with type2 diabetes do not know they have it, although it is a serious condition.Type 2 diabetes is becoming more common due to increasing obesity andfailure to exercise. Gestational diabetes is high blood glucose thatdevelops at any time during pregnancy in a woman who does not havediabetes.

There are many risk factors for type 2 diabetes including, but notlimited to, age over 45 years, family history, heart disease, high bloodcholesterol level, obesity, or lack of exercise. Diabetic symptoms mayinclude, but not be limited to, blurry vision, excessive thirst,fatigue, frequent urination, hunger, or unexplained weight loss

Examination and testing for diabetes usually begins with a urineanalysis to determine glucose and ketones levels. Diagnosing diabetesmay be determined by comparing the following factors: i) fasting bloodglucose level—diabetes is diagnosed if higher than 126 mg/dL on twooccasions.

Levels between 100 and 126 mg/dL are referred to as impaired fastingglucose or pre-diabetes. These levels are considered to be risk factorsfor type 2 diabetes and its complications, ii) oral glucose tolerancetest—diabetes is diagnosed if glucose level is higher than 200 mg/dLafter 2 hours. (This test is used more for type 2 diabetes.), iii)random (non-fasting) blood glucose level—diabetes is suspected if higherthan 200 mg/dL and accompanied by the classic diabetes symptoms ofincreased thirst, urination, and fatigue. (This test must be confirmedwith a fasting blood glucose test.).

C. Epilepsy: In one embodiment, the present invention contemplates amethod for treating epilepsy using an impermeable therapeutic agentdelivery device. In one embodiment, the delivery device providescontrolled release of the agent. In one embodiment, the agent comprisesan anticonvulsant, wherein the anticonvulsant suppresses brain cellfiring rates. In one embodiment, the device is implanted within alocalized area of the brain that is suspected of having localized celldamage.

Epilepsy is a brain disorder involving repeated seizures of any type.Seizure disorders affect about 0.5% of the population. Approximately1.5-5.0% of the population may have a seizure in their lifetime.Epilepsy can affect people of any age. Seizures are episodes ofdisturbed brain function that cause changes in attention or behavior.They are caused by abnormal excited electrical signals in the brain.Sometimes seizures are related to a temporary condition, such asexposure to drugs, withdrawal from certain drugs, or abnormal levels ofsodium or glucose in the blood. In such cases, repeated seizures may notrecur once the underlying problem is corrected. In other cases, injuryto the brain (for example, stroke or head injury) causes brain tissue tobe abnormally excitable. In some people, an inherited abnormalityaffects nerve cells in the brain, which leads to seizures. Some seizuresare idiopathic, which means the cause can not be identified. Suchseizures usually begin between ages 5 and 20, but they can occur at anyage. People with this condition have no other neurological problems, butoften have a family history of seizures or epilepsy.

Disorders affecting the blood vessels, such as stroke and TIA, are themost common cause of seizures after age 60. Degenerative disorders suchas senile dementia Alzheimer type can also lead to seizures.

Some of the more common causes of seizures include but are not limitedto, developmental problems, metabolic abnormalities, brain injury,tumors and brain lesions (such as hematomas), or infections. Theseverity of symptoms can vary greatly, from simple staring spells toloss of consciousness and violent convulsions. For many patients, theevent is the same thing over and over, while some people have manydifferent types of seizures that cause different symptoms each time. Thetype of seizure a person has depends on a variety of many things, suchas the part of the brain affected and the underlying cause of theseizure. An aura consisting of a strange sensation (such as tingling,smell, or emotional changes) occurs in some people prior to eachseizure. Seizures may occur repeatedly without explanation. Risk factorsinclude, but are not limited to, a family history of epilepsy, headinjury, or other condition that causes damage to the brain.

Epileptic seizures may fall under one of several classificationsincluding, generalized seizures (i.e., for example, petit mal and grandmal), partial seizures (i.e., for example, simple and complex).

The diagnosis of epilepsy and seizure disorders requires a history ofrecurrent seizures of any type. A physical examination (including adetailed neuromuscular examination) may be normal, or it may showabnormal brain function related to specific areas of the brain. Forexample, an electroencephalograph (EEG), a reading of the electricalactivity in the brain, may confirm the presence of various types ofseizures. It may, in some cases, indicate the location of the lesioncausing the seizure. EEGs can often be normal in between seizures, so itmay be necessary to do prolonged EEG monitoring. Other tests may includevarious blood tests to rule out other temporary and reversible causes ofseizures, including, but not limited to, a complete blood count, bloodchemistry, blood glucose, liver function, kidney function, infectiousdiseases, or cerebrospinal fluid analysis.

Anti-convulsant oral drugs are normally prescribed to control theseizures. As each individual's response to the drug differs, the initialadministration is carefully monitored and titrated. The type of medicineused depends on seizure type, and dosage may need to be adjusted fromtime to time. Some seizure types respond well to one medication and mayrespond poorly (or even be made worse) by others. Some medications needto be monitored for side effects and blood levels.

Epilepsy that does not respond to the use of several medications iscalled refractory epilepsy. Certain people with this type of epilepsymay benefit from brain surgery to remove the abnormal brain cells thatare causing the seizures. Others may be helped with a vagal nervestimulator, which is implanted in the chest. This stimulator can helpreduce the number of seizures.

D. Macular Degeneration: In one embodiment, the present inventioncontemplates a method for treating macular degeneration using animpermeable therapeutic agent delivery device. In one embodiment, thedelivery device provides controlled release of the agent. In oneembodiment, the agent may be selected from the group comprisingMacugen®, Avastin®, Lucentis®, or Kenalog®. In one embodiment, thedevice is implanted within the vitreous humor of the eye, such that thedevice is free-floating.

Macular degeneration is a disorder that affects the macula (the centralpart of the retina of the eye) causing decreased vision and possibleloss of central vision. The macula is the part of the retina that allowsthe eye to see fine details at the center of the field of vision.Degeneration results from a partial breakdown of the retinal pigmentepithelium (RPE). The RPE is the insulating layer between the retina andthe choroid (the layer of blood vessels behind the retina). The RPE actsas a filter to determine what nutrients reach the retina from thechoroid. Many components of blood are harmful to the retina and are keptaway from the retina by normal RPE.

Breakdown of the RPE interferes with the metabolism of the retina,causing thinning of the retina (the “dry” phase of maculardegeneration). These harmful elements may also cause new blood vessel toform and fluid to leak (the “wet” phase of macular degeneration).

Macular degeneration results in the loss of central visiononly—peripheral fields usually stay normal. Although loss of ability toread and drive may be caused by macular degeneration, the disease doesnot lead to complete blindness. The disease becomes increasingly commonas people age over 50. By age 75, almost 15% of people have thiscondition. Other risk factors are family history, cigarette smoking, andbeing Caucasian.

In general, macular degeneration symptoms usually include, but are notlimited to, blurred, distorted, dim, or absent central vision. Testingto evaluate retinal function may include, but is not limited to, visualacuity, refraction test, pupillary reflex response, slit lampexamination, retinal examination, fluorescein angiography, Amsler grid,optical coherence tomography (OCT), a test that creates a color pictureof the macula or retina

While there is no specific treatment for dry macular degeneration,dietary zinc supplements may slow the progression of the disease.Alternatively, laser photocoagulation (i.e., for example, laser surgeryto stop the leaking in choroidal blood vessels) may be useful in theearly stages of the wet form of the disease. It involves the use of athermal laser, which burns the abnormal, leaky blood vessels and stopsthem from spreading.

Photodynamic therapy may be used in conjunction with verteporfin(Visudyne®), a light-sensitive medication that is conventionallyinjected into a vein in the patient's arm. When a non-thermal laser isshone into the eyes, verteporfin produces a chemical reaction thatdestroys abnormal blood vessels. While the treatment is temporary, itcan be repeated without adverse effect.

Other drugs used to treat the wet form of macular degeneration include,but is not limited to, Macugen, Avastin, Lucentis, and Kenalog.Conventional administration requires direct injection into the eye atregular intervals.

E. Pain Management: In one embodiment, the present inventioncontemplates a method for treating acute and/or chronic pain using animpermeable therapeutic agent delivery device. In one embodiment, thedelivery device provides controlled release of the agent. In oneembodiment, the agent comprises an opioid. In one embodiment, the deviceis implanted within a spinal disc, wherein the disc is suspected ofhaving localized nerve cell damage. Pain is mediated by the peripheraland central nervous systems to identify to a biological organism thesource and severity of an injury or illness. Pain may occur at manydifferent intensities having many different qualitative natures. Forexample, a pain may be of a minimal intensity but having a stablenature. Alternatively, a pain may be of a maximal intensity but havingan unstable nature (i.e., for example, throbbing). Further, the apparentlocation of a particular pain may not accurately reflect the actualsource of the injury or illness (i.e., for example, referred pain).

Pain may occur in almost any part of the body including, but not limitedto, abdomen, ankle, anus, back, bones, breast, ear, elbow, eye, finger,foot, groin, head, heel, hip, joints, knee, leg, muscles, neck, ribcage, shins, shoulder, flank, teeth, wrist, or somatoform. Painmedicines are also called analgesics. Every type of pain medicine hasbenefits and risks. Specific types of pain may respond better to onekind of medication than to another kind. Further, pain medications mayalso be patient-specific, where a specific pain medication may work inone patient but be ineffective in another. Over-the-counter (OTC)medications are good for many types of pain. OTC medicines include, butare not limited to, acetaminophen and nonsteroidal anti-inflammatorydrugs. Acetaminophen is a non-aspirin pain reliever. It can be used tolower a fever and soothe headaches and other common aches and pains.However, acetaminophen does not reduce swelling (inflammation). Thismedicine is easier on the stomach than other pain medications, and it issafer for children. It can, however, be harmful to the liver if you takemore than the recommended dose. NSAIDs include aspirin, naproxen, andibuprofen. These medicines relieve pain, but they also reduceinflammation caused by injury, arthritis, or fever. NSAIDs work byreducing the production of hormone-like substances that cause pain.

Prescription medications may be needed for other types of pain. COX-2inhibitors are a type of prescription painkiller that block aninflammation-promoting substance called COX-2. This class of drugs wasinitially believed to work as well as traditional NSAIDs, but with fewerstomach problems. However, numerous reports of heart attacks and strokehave prompted the FDA to re-evaluate the risks and benefits of theCOX-2s. Patients should ask their doctor whether a COX-2 drug isappropriate and safe for them. Narcotic painkillers (i.e., for example,opioids) are very strong, potentially habit-forming medicines used totreat severe pain. They include, but are not limited to, morphine andcodeine.

F. Parkinson's Disease: In one embodiment, the present inventioncontemplates a method for treating Parkinson's disease using animpermeable therapeutic agent delivery device. In one embodiment, thedelivery device provides controlled release of the agent. In oneembodiment, the agent comprises a dopamine agonist. In one embodiment,the device is implanted within a substantia nigra tissue, wherein thetissue is suspected of having localized cell damage. In one embodiment,the tissue comprises transplanted tissue. In one embodiment, the agentcomprises a contrast agent, wherein the agent facilitates highresolution, localized brain imaging.

Parkinson's disease is a disorder of the brain that leads to shaking(tremors) and difficulty with walking, movement, and coordination. Thedisease affects approximately 2 of every 1,000 people and most oftendevelops after age 50. It is one of the most common neurologic disordersof the elderly. Sometimes Parkinson's disease occurs in younger adults,but is rarely seen in children. It affects both men and women. In somecases, Parkinson's disease occurs within families, especially when itaffects young people. Most of the cases that occur at an older age haveno known cause.

Parkinson's disease occurs when the nerve cells in the part of the brainthat controls muscle movement (i.e., for example, the substantia nigra)are gradually destroyed. The damage gets worse with time. The exactreason that the cells of the brain waste away is unknown. The disordermay affect one or both sides of the body, with varying degrees of lossof function.

Nerve cells within the substantia nigra comprise dopamine as aneurotransmitter. Damage in the area of the brain that controls musclemovement causes a decrease in dopamine production. Too little dopaminedisturbs the balance between nerve-signaling substances (transmitters).Without dopamine, the nerve cells cannot properly send messages. Thisresults in the loss of muscle function.

Some people with Parkinson's disease become severely depressed. This maybe due to loss of dopamine in certain brain areas involved with pleasureand mood. Lack of dopamine can also affect motivation and the ability tomake voluntary movements.

Early loss of mental capacities is uncommon. However, persons withsevere Parkinson's may have overall mental deterioration (includingdementia and hallucinations). Dementia can also be a side effect of someof the medications used to treat the disorder.

Symptoms of Parkinson's disease may include, but be limited to, musclerigidity, unstable, stooped, or slumped-over posture, loss of balance,abnormal gait, slow movements, voluntary movement initiation difficulty,walking initiation difficulty, standing initiation difficulty, myalgia,shaking, tremors, facial expression abnormalities, speech abnormalities,fine motor skill abnormalities, frequent falls, decline in intellectualfunction (may occur, can be severe), or gastrointestinal symptoms (i.e.,for example, constipation).

Diagnosis usually requires a professional subjective evaluation of theexpressed symptomology. Objective tests may be used to rule out otherdisorders that cause similar symptoms in order to perform a differentialdiagnosis.

Currently prescribed medications only control symptoms primarily byincreasing the levels of dopamine in the brain, and do not provide anycurative value. The specific type of medication, the dose, the amount oftime between doses, or the combination of medications taken may need tobe changed from time to time as symptoms change. Many medications cancause severe side effects, so monitoring and follow-up by the healthcare provider is important.

Types of medication usually prescribed for Parkinson's disease includes,but is not limited to, deprenyl, amantadine, levodopa, carbidopa,entacapone, pramipexole, ropinirole, rasagiline, or rotigotine.Additional medications to help reduce symptoms or control side effectsof primary treatment medications include antihistamines,antidepressants, monoamine oxidase inhibitors (MAOIs), and others.

Transplantation of adrenal gland tissue to the brain has been attempted,with variable results. Such transplants are in an attempt to improve thebioavailability of naturally produced dopamine precursors that may helpelevate dopamine levels.

G. Cancer: In one embodiment, the present invention contemplates amethod for treating cancer using an impermeable therapeutic agentdelivery device. In one embodiment, the delivery device providescontrolled release of the agent. In one embodiment, the agent comprisesan antiproliferative. In one embodiment, the device is implanted withina tumor or in proximity therewith. In one embodiment, the device isimplanted within a cardiovascular vessel.

Cancer is generally defined as an uncontrolled growth of abnormal cellsin the body. Cancerous cells may be either malignant or benign. Cancergrows out of normal cells in the body and appears to occur when thegrowth of cells in the body is out of control and cells divide toorapidly. It can also occur when cells lose the ability to undergoapoptosis.

There are many different kinds of cancers. Cancer can develop in almostany organ or tissue, including, but not limited to the lung, colon,breast, skin, bones, or nerve tissue. Specific types of cancer mayinclude but are not limited to, lung cancer, brain cancer, cervicalcancer, uterine cancer, liver cancer, leukemia, Hodgkin's lymphoma,Non-Hodgkin's lymphoma, kidney cancer, ovarian cancer, skin cancer,testicular cancer, thyroid cancer. There are multiple causes of cancers,including but not limited to, radiation, sunlight, tobacco, viruses,chemicals, poisonous mushrooms, or aflatoxins.

The three most common cancers in men in the United States are prostatecancer, lung cancer, and colon cancer. The three most frequentlyoccurring cancers in women in the U.S. are breast, lung and coloncancers. Certain cancers are more common in particular geographic areas.For example, in Japan, there are many cases of gastric cancer, while inthe U.S. this type of cancer is relatively rare. Differences in diet mayplay a role.

Symptoms of cancer depend on the type and location of the tumor. Forexample, lung cancer can cause coughing, shortness of breath, or chestpain, while colon cancer often causes diarrhea, constipation, and bloodin the stool. Some cancers may not have any symptoms at all. In somecancers, such as gallbladder cancer, symptoms often are not presentuntil the disease has reached an advanced stage. In general symptomsthat are common with most cancers include, but are not limited to,fever, chills, night sweats, weight loss, loss of appetite, fatigue, ormalaise.

Examination and tests to identify and/or diagnose cancers vary based onthe type and location of the tumor. Nonetheless, common cancer testsinclude, but are not limited to, computer tomography scanning, completeblood count, blood chemistries, tissue biopsy, or X-ray radiography.Most cancer diagnoses are confirmed by biopsy. Depending on the locationof the tumor, the biopsy may be a simple procedure or a seriousoperation. Most patients with cancer undergo imaging scans to determinethe exact location of the tumor or tumors.

Cancer treatments also vary based on the type, stage and location of aparticular cancer and/or cancerous tumor. The stage of a cancer refersto how much it has grown and whether the tumor has spread from itsoriginal location. If the cancer is confined to one location and has notspread, the goal for treatment would be surgery and cure. This is oftenthe case with skin cancers. If the tumor has spread to local lymph nodesonly, sometimes these can also be removed. If all of the cancer cannotbe removed with surgery, the options for treatment include radiation,chemotherapy, or both. Some cancers require a combination of surgery,radiation, and chemotherapy.

H. Fungal Infections: In one embodiment, the present inventioncontemplates a method for treating a fungus infection using animpermeable therapeutic agent delivery device. In one embodiment, thedelivery device provides controlled release of the agent. In oneembodiment, the agent comprises an antifungal agent. In one embodiment,the device is implanted underneath a toenail. In one embodiment, thedevice is implanted underneath a fingernail. In one embodiment, thedevice is implanted using a twenty-seven (27) gauge needle.

The body normally hosts a variety of bacteria and fungi and some speciesare useful to the body, while others result in infection. Fungi can liveon the dead tissues of the hair, nails, and outer skin layers. Fungalinfections may include, but are not limited to, athlete's foot, jockitch, ringworm, or Tinea capitis. Other fungal infections may alsoinclude yeast-like fungi such as candida. Candida yeast infectionsinclude, but are not limited to, cutaneous candidiasis, diaper rash,oral thrush, or genital rashes.

In particular, fungal nail infections are most often seen in adults andare often quite persistent and refractory to most topical treatments.They often follow fungal infection of the feet. Toenails are affectedmore often than fingernails. People who frequent public swimming pools,gyms, or shower rooms—and people who perspire a great deal—commonly havemold-like infections. The fungi that cause them thrive in warm, moistareas.

Symptoms of a nail fungal infection include, but are not limited to,brittleness, change in nail shape, crumbling of the nail, debris trappedunder the nail, discoloration, detachment, loss of luster and shine, orthickening.

Over-the-counter creams and ointments generally do not help treat thiscondition. Consequently, prescription antifungal medicines may taken bymouth may help clear the fungus in about 50% of patients. However, suchmedicines can cause side effects or may interfere with othermedications. Further, some of the oral medications used to treat fungalinfections of the nail can harm the liver.

Example I Manufacture of a Single Passageway Impermeable Delivery Device

This example describes the manufacture of one embodiment of animpermeable zero order kinetic drug delivery device having a singlepassageway.

Lengths of polyimide tubes were provided having a length of 20 mm and adiameter of 125 microns. At the centre of each tube, a passageway with adiameter of 30 microns was made using standard chemical procedures.

Seven (7) tubes having the optimal passageways were selected and loadedwith a concentrated solution of crystal violet in ethanol by capillarymethod. The tubes were then allowed to stand for 24 hours at roomtemperature to evaporate alcohol from the tubes, such that the tube istightly packed with a solid crystal violet composition.

After taking an initial weight measurement, an average amount of 126micrograms of crystal violet was estimated inside the tubes. The ends ofthe tubes were sealed with a bioglue and dried.

Example II Release Kinetics of a Single Passageway Impermeable DeliveryDevice

This example describes one method that evaluates the release of an agentfrom a single passageway impermeable delivery device.

Single passageway tubes made according to Example I were placed inmicrovials containing 0.26 ml of phosphate buffered saline (0.01 Mphosphate, pH 7.37). The vials were placed in a USP DisintegrationApparatus having dip rate of 30-32 dips per minute. The apparatus wasconnected to a waterbath maintained at 37° C. for the entire duration ofstudy. The buffer was changed every 48 hours, sampled, and analyzed forthe amount of crystal violet released using a UV-Vis Spectrophotometerfor 28 days.

A significant linearity of release of the crystal violet was obtainedfrom this single passageway device (see FIGS. 6 and 7). Additionally,the percentage release when extrapolated to 100% corresponds to thetotal duration of release of approximately 43 years.

Example III Manufacture of a Double Passageway Impermeable DeliveryDevice

This example describes the manufacture of one embodiment of animpermeable zero order kinetic drug delivery device having twopassageways.

Several drug delivery devices were constructed in accordance with inExample I except that two passageways were made located equidistant fromthe tube centre. The optimal seven (7) were selected and loaded withcrystal violet in accordance with Example I.

Example IV Release Kinetics of a Double Passageway Impermeable DeliveryDevice

This example describes one method that evaluates the release of an agentfrom a double passageway impermeable delivery device.

The double passageway tubes made in accordance with Example III weretested for crystal violet release in accordance with Example II. Again,significant linear agent release was obtained from the double passagewayembodiment as seen in FIGS. 6 and 7. Additionally, the percentagerelease when extrapolated to 100% corresponds to the total duration ofrelease of approximately 22 years.

Example V Manufacture of a Triple Passageway Impermeable Delivery Device

This example describes the manufacture of one embodiment of animpermeable zero order kinetic drug delivery device having threepassageways.

Several drug delivery devices were constructed in accordance withExample I except that three passageways were made located equidistantfrom each end of the tube. The optimal seven (7) were selected andloaded with crystal violet in accordance with Example I.

Example VI Release Kinetics of a Triple Passageway Impermeable DeliveryDevice

This example describes one method that evaluates the release of an agentfrom a triple passageway impermeable delivery device.

The triple passageway tubes made in accordance with Example III weretested for crystal violet release in accordance with Example II. Again,significant linear agent release was obtained from the triple passagewayembodiment (FIGS. 6 and 7). Additionally, the percentage release whenextrapolated to 100% corresponds to the total duration of release ofapproximately 15 years.

Example VII Comparative Release Linearity Between Single, Double, andTriple Passageway Delivery Devices

This example compares the linearity data collected in Example II, IV,and VI between the single, double, and triple passageway deliverydevices.

The data shows no differences in the linearity of release rates amongstthe single, double, and triple passageway devices. This data suggeststhat each passageway releases the same amount of agent over timeregardless of the number of passageways present on the surface of thedevice. In this experiment, the passageways in each of the three groupshave similar dimensions and only differ in number of holes on thesurface (FIG. 8).

Example VIII Construction of a Single Outlet Port Impermeable DeliveryDevice

This example describes the manufacture of one embodiment of animpermeable zero order kinetic drug delivery device having a singleoutlet port at the end of the device.

Seven (7) lengths of polyimide tubes were provided having a length of 20mm and a diameter of 125 microns. The tubes were then loaded with aconcentrated solution of crystal violet in ethanol by capillary method.The tubes were then allowed to stand for 24 hours at room temperature toevaporate alcohol from the tubes, such that the tube is tightly packedwith a solid crystal violet composition. One end of the tube was sealedwith a bioglue while the other end was left open.

After taking an initial weight measurement, an average amount of 126micrograms of crystal violet was estimated inside the tubes.

Example IX Release Kinetics of an Outlet Port Impermeable DeliveryDevice

This example describes one method that evaluates the release of an agentfrom a single outlet port impermeable delivery device.

A drug delivery device made in accordance with Example VIII wassubjected to release studies as described in Example II. In particular,the device did not have any surface passageways but allowed to releasefrom one open end. A significant linearity of release of the crystalviolet was obtained over a period of five (5) days as shown in FIG. 9.The percentage release when extrapolated to 100% corresponds to thetotal duration of release of approximately 2 years.

Example X Release Kinetics of an Outlet Port Impermeable Delivery Device

Drug delivery devices were made having one outlet port and one sealedend. In particular, the device did not have any surface passageways butallowed to release from one open end. Three different variation ofdevices were prepared with different inside diameters, as in 200, 400,and 600 microns. Four devices of each type were subjected to releasestudies as described in Example I. Single passageway tubes were placedin micro vials containing 3.0 ml of phosphate buffered saline (0.01 Mphosphate, pH 7.37). The vials were placed in an incubator maintained at37° C. for the entire duration of study. The buffer was changed every 24hours, sampled, and analyzed for the amount of crystal violet releasedusing a UV-Vis Spectrophotometer for seven (7) days. A significantlinearity of release of the crystal violet was obtained over a period ofseven (7) days (FIG. 17).

Example XI Drug Loading of Prednisolone Suspension Using PositivePressure

An ethanolic suspension of prednisolone was prepared by adding 200 mg ofprednisolone to 0.5 ml ethanol. A 1 ml syringe, which was attached tothe touhy borst adapter, was filled with the high density suspension.The polyimide tube (diameter=125 microns) was screwed tightly to theother end of the adapter, and the prednisolone suspension was injectedinto the tube. Afterwards, the ethanol was evaporated by allowing thetubes to stand overnight. The final weight was analyzed using TGA-7. Anet amount of 87.58±11.70 micrograms of prednisolone was loaded into thetubes. The amount of drug loaded per unit length of the tube was5.68±0.65 micrograms/mm. The net amount of drug loaded indicates contentuniformity amongst all the tubes whereas, amount of drug loaded per unitlength indicates the homogeneity of drug distribution inside the tube.

Example XII Drug Loading of Powdered Crystal Violet

A group of polyimide tubes (diameter=1000 microns) were manually loadedwith crystal violet powder. The average amount of crystal violet loadedper unit length in the groups was 5.31±0.28 milligrams/cm.

Although the present invention has been described with severalembodiments, a myriad of changes, variations, alterations,transformations, and modifications may be suggested to one skilled inthe art, and it is intended that the present disclosure encompass suchchanges, variations, alterations, transformation, and modifications asthey fall within the scope of the appended claims.

It is contemplated that any embodiment discussed in this specificationcan be implemented with respect to any method, kit, reagent, orcomposition of the invention, and vice versa. Furthermore, compositionsof the invention can be used to achieve methods of the invention.

It will be understood that particular embodiments described herein areshown by way of illustration and not as limitations of the invention.The principal features of this invention can be employed in variousembodiments without departing from the scope of the invention. Thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, numerous equivalents to the specificprocedures described herein. Such equivalents are considered to bewithin the scope of this invention and are covered by the claims.

All publications and patent applications mentioned in the specificationare indicative of the level of skill of those skilled in the art towhich this invention pertains. All publications and patent applicationsare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

The use of the word “a” or “an” when used in conjunction with the term“comprising” in the claims and/or the specification may mean “one,” butit is also consistent with the meaning of “one or more,” “at least one,”and “one or more than one.” The use of the term “or” in the claims isused to mean “and/or” unless explicitly indicated to refer toalternatives only or the alternatives are mutually exclusive, althoughthe disclosure supports a definition that refers to only alternativesand “and/or.” Throughout this application, the term “about” is used toindicate that a value includes the inherent variation of error for thedevice, the method being employed to determine the value, or thevariation that exists among the study subjects.

As used in this specification and claim(s), the words “comprising” (andany form of comprising, such as “comprise” and “comprises”), “having”(and any form of having, such as “have” and “has”), “including” (and anyform of including, such as “includes” and “include”) or “containing”(and any form of containing, such as “contains” and “contain”) areinclusive or open-ended and do not exclude additional, unrecitedelements or method steps.

The term “or combinations thereof” as used herein refers to allpermutations and combinations of the listed items preceding the term.For example, “A, B, C, or combinations thereof” is intended to includeat least one of: A, B, C, AB, AC, BC, or ABC, and if order is importantin a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB.Continuing with this example, expressly included are combinations thatcontain repeats of one or more item or term, such as BB, AAA, MB, BBC,AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan willunderstand that typically there is no limit on the number of items orterms in any combination, unless otherwise apparent from the context.

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations may be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the method described herein without departing from the concept,spirit and scope of the invention. All such similar substitutes andmodifications apparent to those skilled in the art are deemed to bewithin the spirit, scope and concept of the invention as defined by theappended claims.

1-79. (canceled)
 80. A device for delivery of one or more active agents capable of zero-order delivery kinetics comprising: a housing formed from one impermeable, biocompatible material encompassing a hollow core; one or more passageways of micrometer scale fabricated in the housing and connecting the hollow core and an outer space; a drug supply loaded in the hollow core via a first end of the housing, wherein the drug supply comprises the one or more active agents; and a biocompatible material sealing the first end of the housing.
 81. The device of claim 80, wherein the housing is a tubular housing encompassing the hollow core and the one or more passageways extend through the tubular housing.
 82. The device of claim 80, wherein the homogenous, impermeable, biocompatible housing is smaller than 5 mm in diameter.
 83. The device of claim 80, wherein the one or more passageways have an inner diameter in the range of 1-100 μm, 10-50 μm or 20-30 μm.
 84. The device of claim 80 further comprising multiple housings, each of which comprise one or more passageways to enable individual release rates of therapeutic agents from the housings.
 85. The device of claim 80, wherein the housing comprises multiple partitioned compartments each of which comprises one or more passageways to enable individual release rates of therapeutic agents from the compartments.
 86. The device of claim 80, wherein the passageways are coated or sealed with a biodegradable material to control the timing of the onset of drug release.
 87. The device of claim 80, wherein the device comprises a plurality of enclosures each of which contains an active agent and the release rate from each of which can be controlled by the dimensions of the critical features, such as the size and shape of the enclosure and the number and the size of the passages, and affected by the drug solubility and drug loading density.
 88. The device of claim 80, wherein the device comprises an enclosure which is loaded with multiple active agents and each of the active agents may have an individual release rate as a result of the composite interactions of the drug solubility, drug loading density, dimensions of the critical features, such as the size and shape of the enclosure and the number and the size of the passages.
 89. The device of claim 80, wherein the shape of the one or more holes or perforations is selected from the group consisting of a triangle, a polygon, an undecagon, a trapezium or trapezoid, a quadrilateral, an icosagon, a star polygon, an annulus, a circle, a crescent, an ellipse, an oval, an arbelos, a Reuleaux triangle, a semicircle, a sphere, an Archimedean spiral, an astroid, a deltoid, a super ellipse, and a tomahawk.
 90. The device of claim 80, wherein the hollow core is loaded with a composition or formulation of one or more therapeutic agents which are to be released at their individual release rates
 91. The device of claim 80, wherein the device may optionally be integrated with a microelectronic circuit, wherein the microelectronic circuit comprises at least one of a sensor, a transmitter, a receiver, a transceiver, a switch, a power supply or a light, and wherein the microelectronic circuit is capable of monitoring body analytes and controlling the release of chemical agents or medications.
 92. The device of claim 91, wherein the sensor comprises an analyte sensor wherein the analyte may be selected from the group consisting of an inorganic ion, a small organic molecule, a protein, and a steroid hormone.
 93. The device of claim 92, wherein the protein comprises an insulin protein.
 94. The device of claim 91, wherein a signal from the transmitter is received by a remote detector.
 95. The device of claim 80, wherein the hollow core is filled with one or more active agents in a dosage form selected from the group consisting of a solid dosage form, a liquid dosage form, a semi-solid dosage, a powder, or a hydrogel with or without the use of a polymer, wherein the polymer is a natural polymer, a synthetic polymer or a combination thereof.
 96. The method of claim 95, wherein the natural polymer is selected from the group consisting of anionic polymers, alg-inic acid, pectin, carrageenan, chondroitin sulfate, dextran sulfate, cationic polymers, chitosan, polylysine, amphipathic polymers, collagen, carboxymethyl chitin, fibrin, and neutral polymers, dextran, agarose, pullulan, and combinations and modifications thereof.
 97. The method of claim 95, wherein the synthetic polymer is selected from the group consisting of poly (vinyl alcohol), poly (ethylene oxide), poly (vinyl pyrrolidone), poly (N-iso-propylacrylamide), poly-(caprolactone), poly(hydroxybutyrate), HEMA (hydroxyethylmethacrylate), PMMA (poly(methyl methacrylate), PEMA (poly(ethyl methacrylate), PAAm (polyacrylamide), cyclodextrin, and combinations and modifications thereof.
 98. The device of claim 80, wherein the housing matrix is selected from the group consisting of a polymer, a rubber, a metal, a mineral, a ceramic or a glass, and wherein the passage-way is selected from the group consisting of a hole, a perforation, a channel, an orifice, an aperture, a bore or combinations thereof, and wherein the active agent is selected from the group consisting of a therapeutic drug, a vitamin, a mineral, a saccharide, a lipid, a nucleic acid, a protein, a peptide, and combinations thereof.
 99. The device of claim 80, wherein the therapeutic drug is selected from the group consisting of an analgesic agent, an anti-inflammatory agent, an antihistaminic agent, an antiallergic agent, a central nervous system drug, an antipyretic agent, a respiratory agent, a steroid, a local anesthetic, a sympatho-mimetic agent, an antihypertensive agent, an antipsychotic agent, a calcium antagonist, a muscle relaxant, a vitamin, a cholinergic agonist, an antidepressant, an antispasmodic agent, a mydriatic agent, an anti-diabetic agent, an anorectic agent, an antiulcerative agent, an anti-tumor agent or combinations modifications thereof and, wherein the proteins are selected from the group consisting of an immunoglobulin or fragments thereof, a hormone, an enzyme, a cytokine, a bio-molecule, and combinations and modifications thereof.
 100. The device of claim 80, wherein the device is attached to a medical device.
 101. The device of claim 100, wherein the medical device is selected from the group consisting of a stent, a urinary catheter, an intravascular catheter, a dialysis shunt, a wound drain tube, a skin suture, a vascular graft, an implantable mesh, an intraocular device, an eye buckle, a heart valve, and combinations and modifications thereof.
 102. The device of claim 80, wherein the device is coated with a coating that prevents release of the one or more active agents until the coating is removed, which then causes release of the one or more active agents at a substantially constant rate.
 103. The device of claim 80, wherein the device has a geometrical shape selected from the group consisting of a cuboid, a cube, a sphere, a cone, an oval, and a cylinder.
 104. The device of claim 80, wherein the device may optionally be coated by a polymer, wherein the polymer is selected from the group consisting of polysaccharides, proteins, poly (ethylene glycol), poly(methacrylates), poly(ethylene-co-vinyl acetate), poly(DL-lactide), poly(glycolide), copolymers of lactide and glycolide, polyanhydride copolymers, and combinations and modifications thereof.
 105. The device of claim 80, wherein the device comprises a biocompatible material selected from the group consisting of a polymer, a metal, a mineral, a ceramic, a glass, and combinations and modifications thereof.
 106. The device of claim 80, wherein a number and a size of at least one passageway modulates a rate and an extent of release of the drug.
 107. The device of claim 80, wherein the rate and the extent of drug release is dependent on one or more parameters selected from the group consisting of drug solubility, device dimensions, passageway dimensions, and drug density and wherein the drug release rate is manipulated by changing a parameter selected from the group consisting of one or more holes on the surface, diameter of the holes, distance between the holes, diameter of the tube, length of the tube, solubility of the drug, and the amount of drug supply.
 108. The device of claim 80, wherein the drug supply is selected from a drug depot or a drug reservoir comprising a solid, a liquid, a semi-solid, and a suspension.
 109. The device of claim 108, wherein the drug supply is a member of a biopharmaceutical classification system (BCS) class selected from the group consisting of Class I (High permeability, High solubility); Class II (Low solubility, Low Permeability); Class III (High Solubility, Low Permeability), and Class IV (Low solubility, Low permeability).
 110. The device of claim 108, wherein the drug supply is selected from the group consisting of paclitaxel, rapamycin, sirolimus, zota rolimus, and tacrolimus.
 111. The device of claim 108, wherein the drug supply is selected from the group consisting of digitoxin, digoxin, quinidine, procainamide, propafenone, lidocaine, propanolol, verapamil, diltiazem, nitrogylcerine, isosorbide dinitrate, captopril, enalapril, thiazides, furosemide, spironolactone, pclitaxel, rapamycin, zotarolimus, and tacrolimus and combinations and modifications thereof.
 112. The device of claim 108, wherein the drug supply is selected from the group of opioid agonists consisting of morphine, codeine, thebaine and its derivatives, buprenorphine, papaverine, noscapine, and opioid antagonists consisting of naloxone and naltrexone, and combinations and modifications thereof. 